Carbidopa and L-dopa prodrugs and methods of use

ABSTRACT

The present disclosure relates to (a) carbidopa prodrugs, (b) pharmaceutical combinations and compositions comprising a carbidopa prodrug and/or an L-dopa prodrug, and (c) methods of treating Parkinson&#39;s disease and associated conditions comprising administering a carbidopa prodrug and an L-dopa prodrug to a subject with Parkinson&#39;s disease.

FIELD OF THE INVENTION

The present disclosure relates to (a) carbidopa prodrugs, (b) L-dopaprodrugs, (c) pharmaceutical combinations and compositions comprising acarbidopa prodrug and/or an L-dopa prodrug, and (d) methods of treatingParkinson's disease and associated conditions comprising administering acarbidopa prodrug and an L-dopa prodrug to a subject with Parkinson'sdisease.

BACKGROUND OF THE INVENTION

Parkinson's disease is a chronic and progressive neurodegenerativecondition characterized by reduced levels in the brain of theneurotransmitter dopamine (i.e., 3,4-dihydroxyphenethylamine).Administration of L-dopa (i.e., L-3,4-dihydroxyphenylalanine) currentlyis the most effective therapy for treating a patient with Parkinson'sdisease. L-dopa, which unlike dopamine can cross the blood-brainbarrier, is enzymatically converted in the brain to dopamine resultingin an increase in dopamine levels:

The conversion of L-dopa to dopamine is catalyzed by aromatic L-aminoacid decarboxylase, a ubiquitous enzyme that promotes central as well asperipheral metabolism of L-dopa to dopamine. Due to the peripheralmetabolism of L-dopa, a relatively large dose of L-dopa is required toachieve therapeutically effective dopamine levels in the brain.Administration of such large L-dopa doses results in elevated peripheraldopamine levels that can cause nausea in some patients. To overcomethese problems, L-dopa generally is co-administered with a peripheralaromatic L-amino acid decarboxylase inhibitor such as carbidopa (i.e.,(2S)-3-(3,4-dihydroxyphenyl)-2-hydrazino-2-methylpropanoic acid):

Co-administration of carbidopa with L-dopa inhibits the peripheralmetabolism of L-dopa to dopamine, which significantly reduces the L-dopadose required for a therapeutically effective response and reduces theassociated side effects.

Even when L-dopa and carbidopa are co-administered, however, it isdifficult to consistently maintain the desired dopamine levels in thebrain due to the relatively short half-life of L-dopa in plasma. Inaddition, the tolerance of many patients to variability in dopaminelevels in the brain decreases as the disease progresses. One approachthat has been effective in reducing variability of dopamine levels isthe continuous intestinal delivery of an adjustable dose of anL-dopa/carbidopa gel known by its commercial name, DuoDopa® in Europeand Duopa® in the United States. DuoDopa®/Duopa® is a suspension ofL-dopa/carbidopa monohydrate (4:1 ratio of L-dopa to carbidopamonohydrate) in an aqueous gel (carboxymethyl cellulose sodium) having aviscosity that permits homogeneous distribution of micronized substanceparticles. The gel is delivered to the proximal small intestine througha jejunal tube inserted through a percutaneous endoscopic gastrostomyport. DuoDopa®/Duopa® is packaged in medication cassette reservoirs andcontinuously administered via a software-controlled ambulatory infusionpump. Although L-dopa and carbidopa have been co-administered to treatParkinson's disease for several decades, apharmacokinetically-consistent delivery system that does not requireintestinal insertion is not commercially available.

A major challenge to the development of less invasive or otherwiseimproved modes of administering L-dopa and carbidopa has been thesolubility of those compounds. They each have low aqueous solubility atthe pH range required for infusion. Stable, more highly concentrated,and/or less viscous formulations comprising L-dopa and/or carbidopa (orcompounds capable of in vivo bioconversion to L-dopa and/or carbidopa)are desirable. Such formulations can provide advantages over existingintestinal infusion therapy including: (a) decreasing the volume andimproving the pumpability of the formulation to be delivered to thepatient which also allows for a reduction of the size and weight ofdelivery device; (b) extending the shelf life of the formulation byreducing degradation and improving stability of the formulation; and/or(c) providing the patient with increased flexibility in managing theirtreatment by reducing or eliminating cold storage requirements for theformulation (e.g., longer times to handle the formulation outside ofrefrigerated storage). Such stable, more highly concentrated, and/orless viscous formulations also can be employed in less invasive modes ofadministration (e.g., subcutaneous infusion).

Accordingly, there is a continuing need for improved compositions andmethods that can provide continuous and consistent dopamine levels inthe brain to effectively treat movement disorders such as Parkinson'sdisease. The present disclosure provides such improved compositions andmethods.

SUMMARY OF THE INVENTION

In one aspect, the present disclosure relates to a compoundcorresponding in structure to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂.

In another aspect, the present disclosure relates to a compoundcorresponding in structure Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂.

In another aspect, the present disclosure relates to a pharmaceuticalcombination comprising a first compound corresponding in structure toFormula (I), or a pharmaceutically acceptable salt thereof, and a secondcompound corresponding in structure to Formula (II) or apharmaceutically acceptable salt thereof.

In another aspect, the present disclosure relates to a pharmaceuticalcomposition comprising a first compound corresponding in structure toFormula (I), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier. In certain aspects, thepharmaceutical composition may further comprise a second compoundcorresponding in structure to Formula (II) or a pharmaceuticallyacceptable salt thereof.

In another aspect, the present disclosure relates to a method oftreating Parkinson's disease or an associated condition in a patientcomprising administering to the patient a therapeutically effectiveamount of a pharmaceutical combination comprising a first compoundcorresponding in structure to Formula (I), or a pharmaceuticallyacceptable salt thereof, and a second compound corresponding instructure to Formula (II), or a pharmaceutically acceptable saltthereof. In certain aspects, the method comprises administering thefirst compound corresponding in structure to Formula (I), or apharmaceutically acceptable salt thereof, and the second compoundcorresponding in structure to Formula (II) in a single pharmaceuticalcomposition or in separate pharmaceutical compositions.

Further benefits of the present disclosure will be apparent to oneskilled in the art from reading this patent application. The embodimentsof the disclosure described in the following paragraphs are intended toillustrate the invention and should not be deemed to narrow the scope ofthe invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph of the solubility of L-dopa 4′-monophosphate andcarbidopa 4′-monophosphate at a pH of 7.4 and the solubility of L-dopaand carbidopa.

FIG. 2 is a graph of hydrazine release from a solution of L-dopa4′-monophosphate and carbidopa 4′-phosphate at a ratio of 4:1 at varyingpH levels.

FIG. 3 is a graph comparing hydrazine release between Duopa® and asolution of L-dopa 4′-monophosphate and carbidopa 4′-monophosphate at aratio of 4:1.

FIG. 4 is a time-concentration profile of L-dopa blood levels in ratsafter administration of a combination of L-dopa 3′,4′-diphosphate andcarbidopa 3′,4′-diphosphate at different dose ratios.

FIG. 5 is a time-concentration profile of carbidopa blood levels in ratsafter administration of a combination of L-dopa 3′,4′-diphosphate andcarbidopa 3′,4′-diphosphate at different dose ratios

FIG. 6 is a graph of the steady-state blood levels of L-dopa andcarbidopa in rats after administration of a combination of L-dopa3′,4′-diphosphate and carbidopa 3′,4′-diphosphate at different doseratios.

FIG. 7 is a time-concentration profile of L-dopa blood levels and L-dopa4′-monophosphate blood levels in rats after administration of acombination of L-dopa 4′-monophosphate and carbidopa 4′-monophosphate ata ratio of 4:1.

FIG. 8 is a time-concentration profile of L-dopa blood levels in humansafter administration of Duopa®.

FIG. 9 is a time-concentration profile of carbidopa blood levels andcarbidopa 4′-monophosphate blood levels in rats after administration ofa combination of L-dopa 4′-monophosphate and carbidopa 4′-monophosphateat a ratio of 4:1.

FIG. 10 is a time-concentration profile of L-dopa blood levels inmini-pigs after administration of a combination of L-dopa3′,4′-diphosphate and carbidopa 3′,4′-diphosphate at different doseratios.

FIG. 11 is a time-concentration profile of L-dopa blood levels andL-dopa 4′-monophosphate blood levels in mini-pigs after administrationof a combination of L-dopa 4′-monophosphate and carbidopa4′-monophosphate at a ratio of 15:1.

FIG. 12 is a time-concentration profile of carbidopa blood levels andcarbidopa 4′-monophosphate blood levels in mini-pigs afteradministration of a combination of L-dopa 4′-monophosphate and carbidopa4′-monophosphate at a ratio of 15:1

FIG. 13 is a powder X-ray diffraction pattern of L-dopa 4′-monophosphateanhydrate (i).

FIG. 14 is a powder X-ray diffraction pattern of L-dopa 4′-monophosphateanhydrate (ii).

FIG. 15 is a powder X-ray diffraction pattern of L-dopa3′-monophosphate.

FIG. 16 is a powder X-ray diffraction pattern of L-dopa3′,4′-diphosphate trihydrate.

FIG. 17 is a powder X-ray diffraction pattern of carbidopa4′-monophosphate trihydrate.

FIG. 18 is a powder X-ray diffraction pattern of carbidopa4′-monophosphate dihydrate.

FIG. 19 is a powder X-ray diffraction pattern of carbidopa4′-monophosphate dehydrate.

FIG. 20 is a powder X-ray diffraction pattern of carbidopa3′-monophosphate (i).

FIG. 21 is a powder X-ray diffraction pattern of carbidopa3′-monophosphate (ii).

FIG. 22 is a powder X-ray diffraction pattern of carbidopa3′,4′-diphosphate sodium salt.

DETAILED DESCRIPTION OF THE INVENTION

This written description uses examples to disclose the invention,including the best mode, and also to enable any person skilled in theart to practice the invention, including making and using any of thedisclosed carbidopa phosphate prodrugs or pharmaceutical compositions,and performing any of the disclosed methods or processes. The patentablescope of the invention is defined by the claims, and may include otherexamples that occur to those skilled in the art. Such other examples areintended to be within the scope of the claims if they have elements thatdo not differ from the literal language of the claims, or if theyinclude equivalent elements.

I. Definitions

Section headings as used in this section and the entire disclosure arenot intended to be limiting.

Where a numeric range is recited, each intervening number within therange is explicitly contemplated with the same degree of precision. Forexample, for the range 6 to 9, the numbers 7 and 8 are contemplated inaddition to 6 and 9, and for the range 6.0 to 7.0, the numbers 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitlycontemplated. In the same manner, all recited ratios also include allsub-ratios falling within the broader ratio.

The singular forms “a,” “an” and “the” include plural referents unlessthe context clearly dictates otherwise.

The term “and/or” as used in a phrase such as “A and/or B” herein isintended to include “A and B”, “A or B”, “A”, and “B”.

The term “about” generally refers to a range of numbers that one ofskill in the art would consider equivalent to the recited value (i.e.,having the same function or result). In many instances, the term “about”may include numbers that are rounded to the nearest significant figure.

Unless the context requires otherwise, the terms “comprise,”“comprises,” and “comprising” are used on the basis and clearunderstanding that they are to be interpreted inclusively, rather thanexclusively, and that Applicant intends each of those words to be sointerpreted in construing this patent, including the claims below.

The terms “improve” and “improving” have their plain and ordinarymeaning to one skilled in the art of pharmaceutical or medical sciencesand specifically include ameliorating the effects of Parkinson'sdisease, or decreasing or lessening a side effect of Parkinson'sdisease.

The term “patient” includes mammals and humans, particularly humans.

The term “pharmaceutically acceptable carrier” or “pharmaceuticallyacceptable excipient” refers to any and all solvents, dispersion media,preservatives, antioxidants, coatings, isotonic and absorption delayingagents, and the like, that are compatible with pharmaceuticaladministration.

The term “pharmaceutically acceptable salt” refers to a salt of acompound that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. Such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methyl-bicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; and (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine,dicyclohexylamine, and the like.

The terms “reduce” and “reducing” have their plain and ordinary meaningsto one skilled in the art of pharmaceutical or medical sciences andspecifically include diminishing or decreasing the number ofoccurrences, the duration, or the intensity, of a Parkinson's diseaseside effect, such as dyskinesias or hallucinations.

The term “therapeutically effective amount” means an amount of acompound that, when administered to a patient suffering from orsusceptible to Parkinson's disease or an associated condition issufficient, either alone or in combination with additional therapies, toeffect treatment for Parkinson's disease or the associated condition.The “therapeutically effective amount” will vary depending, for example,on the compound, the condition treated and its severity, and the age andweight of the patient to be treated.

The terms “treat” and “treating” have their plain and ordinary meaningto one skilled in the art of pharmaceutical or medical sciences andspecifically include improving the quality of life or reducing thesymptoms or side effects of Parkinson's disease.

II. Carbidopa and L-Dopa Prodrugs

As previously noted, the inherently low aqueous solubility of L-dopa andcarbidopa at physiologically acceptable pH for infusion presents asignificant technical challenge to the development of improvedpharmaceutical compositions and methods of treatment. Such challengesinclude, for example, difficulties in achieving appropriate dosingvolume and formulation stability within the required pH limitations.These challenges are further complicated by the requirement that thepharmaceutical compositions and methods of treatment providepharmacokinetically-appropriate and pharmacokinetically-consistentcontrol of dopamine levels in the patient's brain.

Prior prodrug approaches have failed for a number of reasons due tothese technical challenges (including insufficient chemical stability,insufficient solubility, in vivo bioconversion issues, and the like) andno L-dopa prodrugs or carbidopa prodrugs for infusion have beensuccessfully commercialized. The prodrugs, pharmaceutical combinationsand compositions, and methods of treatment of the present disclosure,however, have overcome these challenges. They can be used to treatpatients suffering from Parkinson's disease and associated conditionsand do not always require invasive surgery. In various embodiments ofthe present disclosure, the compositions comprise L-dopa and carbidopaprodrugs that convert to L-dopa and carbidopa in vivo which allows fordelivery by continuous administration methods including intragastric,intramuscular, intravenous, and subcutaneous administration. These novelprodrugs, combinations, compositions, and methods of the presentdisclosure represent an advancement in the treatment of Parkinson'sdisease and other related conditions.

A. Carbidopa Prodrugs

In one embodiment, therefore, the present disclosure relates to acompound corresponding in structure to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂. In one aspect, the compound corresponds in structureto Formula (I). In another aspect, the compound is a pharmaceuticallyacceptable salt of a compound corresponding in structure to Formula (I).

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are each independentlyselected from the group consisting of hydrogen and —P(O)(OH)₂; R⁶ ishydrogen or a C₁-C₄-alkyl; and provided that at least one of R¹ and R²is —P(O)(OH)₂. In one aspect, the compound corresponds in structure toFormula (I). In another aspect, the compound is a pharmaceuticallyacceptable salt of a compound corresponding in structure to Formula (I).

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I-a):

or a pharmaceutically acceptable salt thereof. In one aspect, thecompound corresponds in structure to Formula (I-a). In another aspect,the compound is a pharmaceutically acceptable salt of a compoundcorresponding in structure to Formula (I-a).

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I-b):

or a pharmaceutically acceptable salt thereof. In one aspect, thecompound corresponds in structure to Formula (I-b). In another aspect,the compound is a pharmaceutically acceptable salt of a compoundcorresponding in structure to Formula (I-b).

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I-c):

or a pharmaceutically acceptable salt thereof. In one aspect, thecompound corresponds in structure to Formula (I-c). In another aspect,the compound is a pharmaceutically acceptable salt of a compoundcorresponding in structure to Formula (I-c).

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are each independentlyselected from the group consisting of hydrogen and —R⁵—O—P(O)(OH)₂;wherein R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen or a C₁-C₄-alkyl; andprovided that at least one of R¹ and R² is —R⁵—O—P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are each independentlyselected from the group consisting of hydrogen and —R⁵—O—P(O)(OH)₂;wherein R⁵ is methyl; R⁶ is hydrogen or a C₁-C₄-alkyl; and provided thatat least one of R¹ and R² is —R⁵—O—P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are each independentlyselected from the group consisting of hydrogen and —R⁵—O—P(O)(OH)₂;wherein R⁵ is ethyl; R⁶ is hydrogen or a C₁-C₄-alkyl; and provided thatat least one of R¹ and R² is —R⁵—O—P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are each independentlyselected from the group consisting of hydrogen and —R⁵—O—P(O)(OH)₂;wherein R⁵ is propyl; R⁶ is hydrogen or a C₁-C₄-alkyl; and provided thatat least one of R¹ and R² is —R⁵—O—P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are each independentlyselected from the group consisting of hydrogen and —R⁵—O—P(O)(OH)₂;wherein R⁵ is butyl; R⁶ is hydrogen or a C₁-C₄-alkyl; and provided thatat least one of R¹ and R² is —R⁵—O—P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are each independentlyselected from the group consisting of hydrogen, —P(O)(OH)₂, and—R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₂-alkyl; R⁶ is hydrogen; and provided thatat least one of R¹ and R² is —P(O)(OH)₂ or —R⁵—O—P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are each independentlyhydrogen or —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₂-alkyl; R⁶ is hydrogen; andprovided that one of R¹ and R² is —R⁵—O—P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I-d):

or a pharmaceutically acceptable salt thereof. In one aspect, thecompound corresponds in structure to Formula (I-d). In another aspect,the compound is a pharmaceutically acceptable salt of a compoundcorresponding in structure to Formula (I-d).

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I-e):

or a pharmaceutically acceptable salt thereof. In one aspect, thecompound corresponds in structure to Formula (I-e). In another aspect,the compound is a pharmaceutically acceptable salt of a compoundcorresponding in structure to Formula (I-e).

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are each independentlyselected from the group consisting of hydrogen and —P(O)(OH)₂; R⁶ ishydrogen or a C₁-C₄-alkyl; and provided that at least one of R¹ and R²is —P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are each independentlyselected from the group consisting of hydrogen and —P(O)(OH)₂; R⁶ ismethyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are each independentlyselected from the group consisting of hydrogen and —P(O)(OH)₂; R⁶ isethyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are each independentlyselected from the group consisting of hydrogen and —P(O)(OH)₂; R⁶ ispropyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are each independentlyselected from the group consisting of hydrogen and —P(O)(OH)₂; R⁶ isbutyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are each independentlyhydrogen, —P(O)(OH)₂ or —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₂-alkyl; R⁶ is aC₁-C₂-alkyl; and provided that one of R¹ and R² is —P(O)(OH)₂ or—R⁵—O—P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (I-f):

or a pharmaceutically acceptable salt thereof. In one aspect, thecompound corresponds in structure to Formula (I-f). In another aspect,the compound is a pharmaceutically acceptable salt of a compoundcorresponding in structure to Formula (I-f).

B. L-Dopa Prodrugs

In another embodiment, the present disclosure relates to a compoundcorresponding in structure Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂. In one aspect, the compound corresponds in structureto Formula (II). In another aspect, the compound is a pharmaceuticallyacceptable salt of a compound corresponding in structure to Formula(II).

In another embodiment, the present disclosure relates to a compoundcorresponding in structure Formula (II) or a pharmaceutically acceptablesalt thereof, wherein R³ and R⁴ are each independently selected from thegroup consisting of hydrogen and —P(O)(OH)₂; R⁶ is hydrogen or aC₁-C₄-alkyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂.In one aspect, the compound corresponds in structure to Formula (II). Inanother aspect, the compound is a pharmaceutically acceptable salt of acompound corresponding in structure to Formula (II).

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (II-a):

or a pharmaceutically acceptable salt thereof. In one aspect, thecompound corresponds in structure to Formula (II-a). In another aspect,the compound is a pharmaceutically acceptable salt of a compoundcorresponding in structure to Formula (II-a).

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (II-b):

or a pharmaceutically acceptable salt thereof. In one aspect, thecompound corresponds in structure to Formula (II-b). In another aspect,the compound is a pharmaceutically acceptable salt of a compoundcorresponding in structure to Formula (II-b).

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (II-c):

or a pharmaceutically acceptable salt thereof. In one aspect, thecompound corresponds in structure to Formula (II-c). In another aspect,the compound is a pharmaceutically acceptable salt of a compoundcorresponding in structure to Formula (II-c).

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (II) or a pharmaceuticallyacceptable salt thereof, wherein R³ and R⁴ are each independentlyselected from the group consisting of hydrogen and —R⁵—O—P(O)(OH)₂;wherein R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen or a C₁-C₄-alkyl; andprovided that at least one of R³ and R⁴ is —R⁵—O—P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (II), wherein R³ and R⁴ are eachindependently selected from the group consisting of hydrogen and—R⁵—O—P(O)(OH)₂; wherein R⁵ is methyl; R⁶ is hydrogen or a C₁-C₄-alkyl;and provided that at least one of R³ and R⁴ is —R⁵—O—P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (II), wherein R³ and R⁴ are eachindependently selected from the group consisting of hydrogen and—R⁵—O—P(O)(OH)₂; wherein R⁵ is ethyl; R⁶ is hydrogen or a C₁-C₄-alkyl;and provided that at least one of R³ and R⁴ is —R⁵—O—P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (II), wherein R³ and R⁴ are eachindependently selected from the group consisting of hydrogen and—R⁵—O—P(O)(OH)₂; wherein R⁵ is propyl; R⁶ is hydrogen or a C₁-C₄-alkyl;and provided that at least one of R³ and R⁴ is —R⁵—O—P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (II), wherein R³ and R⁴ are eachindependently selected from the group consisting of hydrogen and—R⁵—O—P(O)(OH)₂; wherein R⁵ is butyl; R⁶ is hydrogen or a C₁-C₄-alkyl;and provided that at least one of R³ and R⁴ is —R⁵—O—P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (II-d):

or a pharmaceutically acceptable salt thereof. In one aspect, thecompound corresponds in structure to Formula (II-d). In another aspect,the compound is a pharmaceutically acceptable salt of a compoundcorresponding in structure to Formula (II-d).

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (II-e):

or a pharmaceutically acceptable salt thereof. In one aspect, thecompound corresponds in structure to Formula (II-e). In another aspect,the compound is a pharmaceutically acceptable salt of a compoundcorresponding in structure to Formula (II-e).

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (II) or a pharmaceuticallyacceptable salt thereof, wherein R³ and R⁴ are each independentlyselected from the group consisting of hydrogen and —P(O)(OH)₂; R⁶ ishydrogen or a C₁-C₄-alkyl; and provided that at least one of R³ and R⁴is —P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (II) or a pharmaceuticallyacceptable salt thereof, wherein R³ and R⁴ are each independentlyselected from the group consisting of hydrogen and —P(O)(OH)₂; R⁶ ismethyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (II) or a pharmaceuticallyacceptable salt thereof, wherein R³ and R⁴ are each independentlyselected from the group consisting of hydrogen and —P(O)(OH)₂; R⁶ isethyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (II) or a pharmaceuticallyacceptable salt thereof, wherein R³ and R⁴ are each independentlyselected from the group consisting of hydrogen and —P(O)(OH)₂; R⁶ ispropyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (II) or a pharmaceuticallyacceptable salt thereof, wherein R³ and R⁴ are each independentlyselected from the group consisting of hydrogen and —P(O)(OH)₂; R⁶ isbutyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂.

In another embodiment, the present disclosure relates to a compoundcorresponding in structure to Formula (II) or a pharmaceuticallyacceptable salt thereof, wherein R³ is hydrogen; R⁴ is —P(O)(OH)₂; andR⁶ is methyl.

III. Intermediates

New synthesis routes disclosed herein for making L-dopa phosphates andcarbidopa phosphates have led to the following new intermediatecompounds:

As used herein, “Bn” refers to a benzyl group and “Cbz” refers to acarboxybenzyl group.

IV. Pharmaceutical Combinations/Compositions

The present disclosure also relates to pharmaceutical combinations andcompositions comprising a carbidopa prodrug and/or an L-dopa prodrug.

In some embodiments, the pharmaceutical compositions comprise acarbidopa prodrug. In other embodiments, the pharmaceutical compositionscomprise an L-dopa prodrug. In still other embodiments, thepharmaceutical compositions comprise both a carbidopa prodrug and anL-dopa prodrug.

The carbidopa and L-dopa prodrugs disclosed herein (and theirpharmaceutically acceptable salts) can be formulated in the samepharmaceutical composition or can be present in separate pharmaceuticalcompositions. For example, a pharmaceutical combination disclosed hereincan comprise a carbidopa prodrug in a first pharmaceutical compositionand an L-dopa prodrug in a separate, second pharmaceutical composition.Alternatively, the pharmaceutical combination can comprise a carbidopaprodrug and L-dopa prodrug in the same pharmaceutical composition.

A. First Compound and Second Compound

In one embodiment, the pharmaceutical composition comprises a firstcompound corresponding in structure to Formula (I):

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier; wherein R¹ and R² are each independently selectedfrom the group consisting of hydrogen, —P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂;R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen or a C₁-C₄-alkyl; and provided thatat least one of R¹ and R² is —P(O)(OH)₂ or —R⁵—O—P(O)(OH)₂. In oneaspect, the composition comprises a first compound corresponding instructure to Formula (I). In another aspect, the composition comprises apharmaceutically acceptable salt of the first compound corresponding instructure to Formula (I).

In another embodiment, the pharmaceutical composition comprises a firstcompound corresponding in structure to Formula (I-a) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In one aspect, the composition comprises a firstcompound corresponding in structure to Formula (I-a). In another aspect,the composition comprises a pharmaceutically acceptable salt of thefirst compound corresponding in structure to Formula (I-a).

In another embodiment, the pharmaceutical composition comprises a firstcompound corresponding in structure to Formula (I-b) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In one aspect, the composition comprises a firstcompound corresponding in structure to Formula (I-b). In another aspect,the composition comprises a pharmaceutically acceptable salt of thefirst compound corresponding in structure to Formula (I-b).

In another embodiment, the pharmaceutical composition comprises a firstcompound corresponding in structure to Formula (I-c) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In one aspect, the composition comprises a firstcompound corresponding in structure to Formula (I-c). In another aspect,the composition comprises a pharmaceutically acceptable salt of thefirst compound corresponding in structure to Formula (I-c).

In another embodiment, the pharmaceutical composition comprises a firstcompound corresponding in structure to Formula (I-d) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In one aspect, the composition comprises a firstcompound corresponding in structure to Formula (I-d). In another aspect,the composition comprises a pharmaceutically acceptable salt of thefirst compound corresponding in structure to Formula (I-d).

In another embodiment, the pharmaceutical composition comprises a firstcompound corresponding in structure to Formula (I-e) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In one aspect, the composition comprises a firstcompound corresponding in structure to Formula (I-e). In another aspect,the composition comprises a pharmaceutically acceptable salt of thefirst compound corresponding in structure to Formula (I-e).

In another embodiment, the pharmaceutical composition comprises a firstcompound corresponding in structure to Formula (I-f) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In one aspect, the composition comprises a firstcompound corresponding in structure to Formula (I-f). In another aspect,the composition comprises a pharmaceutically acceptable salt of thefirst compound corresponding in structure to Formula (I-f).

In one embodiment, the pharmaceutical composition comprises a secondcompound corresponding in structure to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂. In one aspect, the composition comprises a secondcompound corresponding in structure to Formula (II). In another aspect,the composition comprises a pharmaceutically acceptable salt of thefirst compound corresponding in structure to Formula (II).

In another embodiment, the pharmaceutical composition comprises a secondcompound corresponding in structure to Formula (II-a) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In one aspect, the composition comprises a secondcompound corresponding in structure to Formula (II-a). In anotheraspect, the composition comprises a pharmaceutically acceptable salt ofthe second compound corresponding in structure to Formula (II-a).

In another embodiment, the pharmaceutical composition comprises a secondcompound corresponding in structure to Formula (II-b) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In one aspect, the composition comprises a secondcompound corresponding in structure to Formula (II-b). In anotheraspect, the composition comprises a pharmaceutically acceptable salt ofthe second compound corresponding in structure to Formula (II-b).

In another embodiment, the pharmaceutical composition comprises a secondcompound corresponding in structure to Formula (II-c) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In one aspect, the composition comprises a secondcompound corresponding in structure to Formula (II-c). In anotheraspect, the composition comprises a pharmaceutically acceptable salt ofthe second compound corresponding in structure to Formula (II-c).

In another embodiment, the pharmaceutical composition comprises a secondcompound corresponding in structure to Formula (II-d) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In one aspect, the composition comprises a secondcompound corresponding in structure to Formula (II-d). In anotheraspect, the composition comprises a pharmaceutically acceptable salt ofthe second compound corresponding in structure to Formula (II-d).

In another embodiment, the pharmaceutical composition comprises a secondcompound corresponding in structure to Formula (II-e) or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier. In one aspect, the composition comprises a secondcompound corresponding in structure to Formula (II-e). In anotheraspect, the composition comprises a pharmaceutically acceptable salt ofthe second compound corresponding in structure to Formula (II-e).

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂; and

-   -   the second compound corresponds in structure to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂.

The composition may independently comprise the first compound and thesecond compound as either the free form of the compound or apharmaceutically acceptable salt of the compound. In one aspect, thecomposition comprises the free form of the first compound. In anotheraspect, the composition comprises a pharmaceutically acceptable salt ofthe first compound. In another aspect, the composition comprises thefree form of the second compound. In another aspect, the compositioncomprises a pharmaceutically acceptable salt of the second compound. Inanother aspect, the composition comprises the free form of the firstcompound and the free form of the second compound. In another aspect,the composition comprises a pharmaceutically acceptable salt of thefirst compound and a pharmaceutically acceptable salt of the secondcompound.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-a) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-b) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-c) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-d) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-e) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-f) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂; and

-   -   the second compound corresponds in structure to Formula (II-a)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂; and

-   -   the second compound corresponds in structure to Formula (II-b)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂; and

-   -   the second compound corresponds in structure to Formula (II-c)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂; and

-   -   the second compound corresponds in structure to Formula (II-d)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂; and

-   -   the second compound corresponds in structure to Formula (II-e)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-a): or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-a)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-b) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-a)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-c) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-a)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-d) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-a)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-e) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-a)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-f) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-a)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-a) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-b)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-b) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-b)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-c) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-b)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-d) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-b)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-e) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-b)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-f) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-b)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-a) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-c)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-b) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-c)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-c) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-c)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-d) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-c)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-e) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-c)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-f) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-c)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-a) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-d)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-b) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-d)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-c) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-d)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-d) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-d)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-e) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-d)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-f) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-d)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-a) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-e)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-b) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-e)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-c) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-e)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-d) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-e)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-e) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-e)        or a pharmaceutically acceptable salt thereof.

In another embodiment, the pharmaceutical composition comprises a firstcompound, a second compound, and a pharmaceutically acceptable carrier,wherein:

-   -   the first compound corresponds in structure to Formula (I-f) or        a pharmaceutically acceptable salt thereof; and    -   the second compound corresponds in structure to Formula (II-e)        or a pharmaceutically acceptable salt thereof.

The pharmaceutical compositions of the present disclosure comprisingboth the first compound and the second compound generally will comprisethe first compound and the second compound at a weight ratio from about1:1 to about 1:50. In one aspect, the weight ratio is from about 1:2 toabout 1:15. In another aspect, the weight ratio is from about 1:4 toabout 1:10. In another aspect, the weight ratio is about 1:4. In anotheraspect, the weight ratio is about 1:7.5. In another aspect, the weightratio is about 1:10.

B. Additional Excipients

The pharmaceutical compositions of the present disclosure optionallycomprise one or more additional pharmaceutically acceptable excipients.The term “excipient” refers to any substance, not itself a therapeuticagent, used as a carrier or vehicle for delivery of a therapeutic agentto a subject or added to a pharmaceutical composition to improve itshandling or storage properties or to permit or facilitate formation of aunit dose of the composition.

Excipients include, for example, antioxidants, agents to adjust the pHand osmolarity, preservatives, thickening agents, colorants, bufferingagents, bacteriostats, and stabilizers. A given excipient, if present,generally will be present in an amount of about 0.001% to about 95%,about 0.01% to about 80%, about 0.02% to about 25%, or about 0.3% toabout 10%, by weight.

In one embodiment, the pharmaceutical compositions optionally comprisean antioxidant. Suitable antioxidants for use in the pharmaceuticalcompositions include, for example, butylated hydroxytoluene, butylatedhydroxyanisole, potassium metabisulfite, and the like.

In one embodiment, the pharmaceutical compositions optionally comprise abuffering agent. Buffering agents include agents that reduce pH changes.Suitable classes of buffering agents for use in various embodiments ofthe present invention comprise a salt of a Group IA metal including, forexample, a bicarbonate salt of a Group IA metal, a carbonate salt of aGroup IA metal, an alkaline or alkali earth metal buffering agent, analuminum buffering agent, a calcium buffering agent, a sodium bufferingagent, or a magnesium buffering agent. Suitable buffering agents furtherinclude carbonates, phosphates, bicarbonates, citrates, borates,acetates, phthalates, tartrates, succinates of any of the foregoing, forexample, sodium or potassium phosphate, citrate, borate, acetate,bicarbonate and carbonate.

C. Dosage Forms

Solid Composition

In one embodiment, the pharmaceutical composition is a solidcomposition.

In another embodiment, the pharmaceutical composition is a solidcomposition that is suitable for oral administration. The first andsecond compound may be present as independent, separate solid dosageforms or combined in the same solid dosage form. Suitable solid dosageforms include capsules, tablets, pills, powders and granules. In suchsolid dosage forms, the first and/or second compound may be mixed withat least one inert, pharmaceutically acceptable excipient or carrier,such as sodium citrate or dicalcium phosphate and/or a) fillers orextenders such as starches, lactose, sucrose, glucose, mannitol andsilicic acid; b) binders such as carboxymethylcellulose, alginates,gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such asglycerol; d) disintegrating agents such as agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, certain silicates and sodiumcarbonate; e) solution retarding agents such as paraffin; f) absorptionaccelerators such as quaternary ammonium compounds; g) wetting agentssuch as cetyl alcohol and glycerol monostearate; h) absorbents such askaolin and bentonite clay and i) lubricants such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate and mixtures thereof. In the case of capsules, tablets andpills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The first and/or second compounds can also be in micro-encapsulated form(separately or together), if appropriate, with one or more of theabove-mentioned carriers.

Liquid Composition

In one embodiment, the pharmaceutical composition is a liquidcomposition. In one aspect, the composition comprises water and issuitable for infusion.

In another embodiment, the pharmaceutical composition is a liquidcomposition that is suitable for intragastric, intestinal (e.g.,intraduodenum, intrajejunum), intranasal, subcutaneous, intramuscular orintravenous administration. In one aspect, the composition is suitablefor intragastric administration. In another aspect, the composition issuitable for subcutaneous administration. In another aspect, thecomposition is suitable for intramuscular administration. In anotheraspect, the composition is suitable for intravenous administration. Inanother aspect, the composition is suitable for intestinaladministration. In another aspect, the composition is suitable forintraduodenum administration. In another aspect, the composition issuitable for intrajejunum administration. In another aspect, thecomposition is suitable for intranasal administration.

In another embodiment, the pharmaceutical composition is an aqueouspharmaceutical composition having an L-dopa prodrug concentration of atleast about 5 mg/mL. In one aspect, the L-dopa prodrug concentration isat least about 10 mg/mL. In another aspect, the L-dopa prodrugconcentration is at least about 20 mg/mL. In another aspect, the L-dopaprodrug concentration is at least about 30 mg/mL. In another aspect, theL-dopa prodrug concentration is at least about 50 mg/mL. In anotheraspect, the L-dopa prodrug concentration is at least about 100 mg/mL. Inanother aspect, the L-dopa prodrug concentration is at least about 150mg/mL. In another aspect, the L-dopa prodrug concentration is at leastabout 200 mg/mL. In another aspect, the L-dopa prodrug concentration isat least about 250 mg/mL. In another aspect, the L-dopa prodrugconcentration is at least about 300 mg/mL. In another aspect, the L-dopaprodrug concentration is at least about 350 mg/mL. In another aspect,the L-dopa prodrug concentration is at least about 400 mg/mL. Inparticular, the above L-dopa prodrug concentrations may be L-dopaphosphate prodrug concentrations, more particularly L-dopa3′-monophosphate prodrug, L-dopa 4′-monophosphate prodrug and/or L-dopa3′,4′-diphosphate prodrug concentrations.

In another embodiment, the pharmaceutical composition is an aqueouspharmaceutical composition having a carbidopa prodrug concentration ofat least about 5 mg/mL. In one aspect, the carbidopa prodrugconcentration is at least about 10 mg/mL. In another aspect, thecarbidopa prodrug concentration is at least about 20 mg/mL. In anotheraspect, the carbidopa prodrug concentration is at least about 30 mg/mL.In another aspect, the carbidopa prodrug concentration is at least about50 mg/mL. In another aspect, the carbidopa prodrug concentration is atleast about 100 mg/mL. In another aspect, the carbidopa prodrugconcentration is at least about 150 mg/mL. In another aspect, thecarbidopa prodrug concentration is at least about 200 mg/mL. Inparticular, the above carbidopa prodrug concentrations may be carbidopaphosphate prodrug concentrations, more particularly carbidopa3′-monophosphate prodrug, carbidopa 4′-monophosphate prodrug and/orcarbidopa 3′,4′-diphosphate prodrug concentrations.

D. pH Level

In one embodiment, the pharmaceutical compositions may have a pH of≧˜2.0, ≧˜2.5, ≧˜3.0, ≧˜3.5, ≧˜4.0, ≧˜4.5, ≧˜5.0, ≧˜5.5, ≧˜6.0, ≧˜6.2,≧˜6.4, ≧˜6.5, ≧˜6.6, ≧˜6.8, ≧˜7.0, ≧˜7.1, ≧˜7.2, ≧˜7.3, ≧˜7.4, ≧˜7.5,≧˜7.6, ≧˜7.7, ≧˜7.8, ≧˜7.9, ≧˜8.0, ≧˜8.2, ≧˜8.4, ≧˜8.6, ≧˜8.8, or ≧˜9.0.Particularly, the pH is ≧˜7.4. Ranges expressly disclosed includecombinations of any of the above-enumerated values, e.g., ˜2.0 to ˜7.5,˜6.0 to ˜9.0, ˜6.4 to ˜7.7, ˜7.0 to ˜7.9, ˜7.3 to ˜8.2, etc. In oneaspect the pH is from about 2 to about 8. In one aspect, the pH is fromabout 2.0 to about 7.5. In another aspect, the pH is from about 3.0 toabout 7.5. In another aspect, the pH is from about 4.0 to about 7.5. Inanother aspect, the pH is from about 5.0 to about 7.5. In anotheraspect, the pH is from about 6.0 to about 7.5.

E. Stability

In another embodiment, the first compound (e.g., the phosphate prodrugs)and the second compound (e.g., the phosphate prodrugs) in thepharmaceutical compositions advantageously may remain stable in liquidcompositions (e.g., aqueous solutions) at the above-described pHs for≧˜24 hours, ≧˜36 hours, ≧˜48 hours, ≧˜60 hours, ≧˜72 hours, ≧˜84 hours,≧˜96 hours, ≧˜108 hours, ≧˜120 hours, ≧˜132 hours, ≧˜136 hours, ≧˜144hours, ≧˜156 hours, ≧˜168 hours, or ≧˜180 hours. Particularly, thepharmaceutical compositions may remain stable in aqueous solutions for≧˜24 hours at a pH of ˜6 to ˜8. Ranges expressly disclosed includecombinations of any of the above-enumerated values, e.g., ˜24 hours to˜180 hours, ˜24 hours to ˜168 hours, ≧˜36 hours to ˜72 hours, etc. Suchincreased stability is important for liquid compositions of thepharmaceutical compositions because typically the liquid compositionsare stored prior to administration (e.g., intragastric, subcutaneous,intrajejunum, intranasal, intramuscular and/or intravenous), and thus,the first compound and the second compound must remain stable and notdegrade significantly during the course of storage.

F. Solubility

In another embodiment, the first compound (e.g., the phosphate prodrugs)and the second compound (e.g., the phosphate prodrugs) in thepharmaceutical compositions unexpectedly have increased solubility inliquid compositions (e.g., aqueous solutions). For example, the firstcompound and/or the second compound may have a solubility at a pH ofabout ˜5 to ˜8, or more particularly at about a neutral pH of about 6.9to about 7.5, of ≧˜90 mg/mL, ≧˜100 mg/mL, ≧˜110 mg/mL, ≧˜120 mg/mL,≧˜130 mg/mL, ≧˜140 mg/mL, ≧˜150 mg/mL, ≧˜160 mg/mL, ≧˜170 mg/mL, ≧˜180mg/mL, ≧˜190 mg/mL, ≧˜200 mg/mL, ≧˜210 mg/mL, ≧˜220 mg/mL, ≧˜230 mg/mL,≧˜240 mg/mL, ≧˜250 mg/mL, ≧˜260 mg/mL, ≧˜270 mg/mL, ≧˜280 mg/mL, ≧˜290mg/mL, ≧˜300 mg/mL, ≧˜310 mg/mL, ≧˜320 mg/mL, ≧˜330 mg/mL, ≧˜340 mg/mL,≧˜350 mg/mL, ≧˜360 mg/mL, ≧˜370 mg/mL, ≧˜380 mg/mL, ≧˜390 mg/mL, ≧˜400mg/mL, ≧˜410 mg/mL, ≧˜420 mg/mL, ≧˜430 mg/mL, ≧˜440 mg/mL, ≧˜450 mg/mL,≧˜460 mg/mL, ≧˜470 mg/mL, ≧˜480 mg/mL, ≧˜490 mg/mL, or ≧˜500 mg/mL.Ranges expressly disclosed include combinations of any of theabove-enumerated values, e.g., ˜90 mg/mL to ˜500 mg/mL, ˜100 mg/mL to˜300 mg/mL, ˜200 mg/mL to ˜500 mg/mL, etc. In particular, the firstcompound has a solubility at a neutral pH, for example of about 7.4, of≧˜160 mg/mL, particularly ≧˜200 mg/mL. In particular, the secondcompound has a solubility at a neutral pH, for example of about 7.4, of≧˜370 mg/mL, particularly ≧˜400 mg/mL. This increased solubility allowsfor higher concentrations of the first compound and/or second compoundin the pharmaceutical composition, which leads to more effective andhigher systemic levels of the first compound and/or second compound onceadministered to a patient.

G. Hydrazine Release

The first compound (e.g., the phosphate prodrugs) and/or second compound(e.g., the phosphate prodrugs) may release amounts of hydrazine, whichis a carcinogen. Thus, it is important to reduce the release ofhydrazine from the pharmaceutical compositions. It has been unexpectedlyfound that the pharmaceutical compositions described herein at a pH of˜5 to ˜8 (e.g., 7.4) release hydrazine in amounts of ≧˜60 ppm/hr, ≧˜55ppm/hr, ≧˜50 ppm/hr, ≧˜45 ppm/hr, ≧˜40 ppm/hr, ≧˜35 ppm/hr, ≧˜30 ppm/hr,≧˜25 ppm/hr, ≧˜20 ppm/hr, ≧˜15 ppm/hr, ≧˜10 ppm/hr, ≧˜5 ppm/hr, ≧˜4ppm/hr, ≧˜3 ppm/hr, ≧˜2 ppm/hr, ≧˜1 ppm/hr, or ≧˜0.5 ppm/hr. Rangesexpressly disclosed include combinations of any of the above-enumeratedvalues, e.g., ˜0.5 to ˜60 ppm/hr, ˜1 ppm/hr to ˜40 ppm/hr, ˜1 ppm/hr to˜10 ppm/hr, ˜2 ppm/hr to ˜4 ppm/hr, etc. Particularly, thepharmaceutical compositions release less than ˜1 ppm/hr of hydrazine.

H. Ready-to-Use

In still other embodiments, the present disclosure relates to aready-to-use vial or cartridge or container or enclosure suitable forliquid pharmaceutical dosage formulation containment. Such containmentmay serve the function of holding a liquid formulation containing one ormore carbidopa prodrugs and/or one or more L-dopa prodrugs. The vialscan also serve as storage for powder forms of the carbidopa prodrug(s)and/or L-dopa prodrug(s) such that the vial can be in a ready to useformat wherein reconstitution with an aqueous vehicle results in a readyto withdraw or load injection to the patient.

I. Pharmaceutical Combinations

As mentioned above, a pharmaceutical combination comprising the firstcompound and the second compound is also disclosed herein. The firstcompound or pharmaceutically acceptable salt thereof, and the secondcompound or pharmaceutically acceptable salt thereof can both be presentin one pharmaceutical composition or can be present in separatepharmaceutical compositions. If separate they can be co-administered asmore fully discussed herein.

Thus, in one embodiment a pharmaceutical combination comprising a firstcompound corresponding in structure to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂; and

-   -   a second compound corresponding in structure Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂ is provided herein.V. Methods of Treatment

The present disclosure further relates to methods of treatingParkinson's disease and associated conditions comprising administeringan effective amount of a carbidopa prodrug and an L-dopa prodrug to apatient.

In some embodiments, the methods of treating Parkinson's disease andassociated conditions include providing a rescue therapy for treatmentof Parkinson's disease and associated conditions. The term “rescuetherapy” as used herein is any acute and intermittent therapy that maybe used to treat the sudden re-immergence of motor symptoms (e.g. sudden“off” episode or “end-of-dose wearing off” and unpredictable “on/off”episodes). Patients with disabling motor complications can cycle between“off” time, which is defined as periods of poor mobility, slowness, andstiffness, and “on” time, which is defined as periods of good motorsystem control without troublesome dyskinesia.

In some embodiments, the carbidopa phosphate prodrug and the L-dopaprodrug are administered to the patient in the form of a pharmaceuticalcomposition comprising both prodrugs. In other embodiments, thecarbidopa prodrug and the L-dopa prodrug are separately administered tothe patient.

A. First Compound and Second Compound and Combinations Thereof

In one embodiment, the present disclosure relates to a method oftreating a condition in a subject (e.g. patient) in need of suchtreatment, wherein the method comprises administering to the patient apharmaceutical combination comprising a first compound and a secondcompound, wherein:

-   -   the first compound corresponds in structure to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂;

-   -   the second compound corresponds in structure to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; wherein R⁵ is a C₁-C₄-alkyl; R⁶ ishydrogen or a C₁-C₄-alkyl; and provided that at least one of R³ and R⁴is —P(O)(OH)₂ or —R⁵—O—P(O)(OH)₂.

In one embodiment, the first compound and the second compound areadministered in amounts that together provide a therapeutically effectfor the subject (e.g. patient).

In one embodiment, the first compound corresponds in structure toFormula (I-a), and the second compound corresponds in structure toFormula (II-a).

In another embodiment, the first compound corresponds in structure toFormula (I-b), and the second compound corresponds in structure toFormula (II-a).

In another embodiment, the first compound corresponds in structure toFormula (I-c), and the second compound corresponds in structure toFormula (II-a).

In another embodiment, the first compound corresponds in structure toFormula (I-d), and the second compound corresponds in structure toFormula (II-a).

In another embodiment, the first compound corresponds in structure toFormula (I-e), and the second compound corresponds in structure toFormula (II-a).

In another embodiment, the first compound corresponds in structure toFormula (I-f), and the second compound corresponds in structure toFormula (II-a).

In another embodiment, the first compound corresponds in structure toFormula (I-a), and the second compound corresponds in structure toFormula (II-b).

In another embodiment, the first compound corresponds in structure toFormula (I-b), and the second compound corresponds in structure toFormula (II-b).

In another embodiment, the first compound corresponds in structure toFormula (I-c), and the second compound corresponds in structure toFormula (II-b).

In another embodiment, the first compound corresponds in structure toFormula (I-d), and the second compound corresponds in structure toFormula (II-b).

In another embodiment, the first compound corresponds in structure toFormula (I-e), and the second compound corresponds in structure toFormula (II-b).

In another embodiment, the first compound corresponds in structure toFormula (I-f), and the second compound corresponds in structure toFormula (II-b).

In another embodiment, the first compound corresponds in structure toFormula (I-a), and the second compound corresponds in structure toFormula (II-c).

In another embodiment, the first compound corresponds in structure toFormula (I-b), and the second compound corresponds in structure toFormula (II-c).

In another embodiment, the first compound corresponds in structure toFormula (I-c), and the second compound corresponds in structure toFormula (II-c).

In another embodiment, the first compound corresponds in structure toFormula (I-d), and the second compound corresponds in structure toFormula (II-c).

In another embodiment, the first compound corresponds in structure toFormula (I-e), and the second compound corresponds in structure toFormula (II-c).

In another embodiment, the first compound corresponds in structure toFormula (I-f), and the second compound corresponds in structure toFormula (II-c).

In another embodiment, the first compound corresponds in structure toFormula (I-a), and the second compound corresponds in structure toFormula (II-d).

In another embodiment, the first compound corresponds in structure toFormula (I-b), and the second compound corresponds in structure toFormula (II-d).

In another embodiment, the first compound corresponds in structure toFormula (I-c), and the second compound corresponds in structure toFormula (II-d).

In another embodiment, the first compound corresponds in structure toFormula (I-d), and the second compound corresponds in structure toFormula (II-d).

In another embodiment, the first compound corresponds in structure toFormula (I-e), and the second compound corresponds in structure toFormula (II-d).

In another embodiment, the first compound corresponds in structure toFormula (I-f), and the second compound corresponds in structure toFormula (II-d).

In another embodiment, the first compound corresponds in structure toFormula (I-a), and the second compound corresponds in structure toFormula (II-e).

In another embodiment, the first compound corresponds in structure toFormula (I-b), and the second compound corresponds in structure toFormula (II-e).

In another embodiment, the first compound corresponds in structure toFormula (I-c), and the second compound corresponds in structure toFormula (II-e).

In another embodiment, the first compound corresponds in structure toFormula (I-d), and the second compound corresponds in structure toFormula (II-e).

In another embodiment, the first compound corresponds in structure toFormula (I-e), and the second compound corresponds in structure toFormula (II-e).

In another embodiment, the first compound corresponds in structure toFormula (I-f), and the second compound corresponds in structure toFormula (II-e).

B. Conditions Treated

In one embodiment, the condition treated by administering the firstcompound and the second compound is Parkinson's disease.

In another embodiment, the condition treated by administering the firstcompound and the second compound is sleep disturbance in a patient withParkinson's disease (i.e., a method of reducing sleep disturbance in apatient with Parkinson's disease).

In another embodiment, the condition treated by administering the firstcompound and the second compound is impaired motor performance in apatient with Parkinson's disease (i.e., a method of improving motorperformance in a patient with Parkinson's disease).

In another embodiment, the condition treated by administering the firstcompound and the second compound is nighttime disability in a patientwith Parkinson's disease (i.e., a method of reducing nighttimedisabilities in a patient with Parkinson's disease).

In another embodiment, the first compound and the second compound areadministered to treat motor fluctuations in a patient with Parkinson'sdisease.

In another embodiment, the first compound and the second compound areadministered to treat dyskinesia in a patient with Parkinson's disease.

In another embodiment, the first compound and the second compound areadministered to delay the onset of motor fluctuations in a patient withParkinson's disease.

In another embodiment, the first compound and the second compound areadministered to delay the onset of dyskinesia in a patient withParkinson's disease.

C. Administering a Pharmaceutical Composition

In one embodiment, the present disclosure relates to a method oftreating a condition in need of treatment, wherein the method comprisesadministering to a subject (e.g. patient) a therapeutically effectiveamount of a pharmaceutical composition of the present disclosure.

In one embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-a), and a secondcompound corresponding in structure to Formula (II-a).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-b), and a secondcompound corresponding in structure to Formula (II-a).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-c), and a secondcompound corresponding in structure to Formula (II-a).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-d), and a secondcompound corresponding in structure to Formula (II-a).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-e), and a secondcompound corresponding in structure to Formula (II-a).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-f), and a secondcompound corresponding in structure to Formula (II-a).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-a), and a secondcompound corresponding in structure to Formula (II-b).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-b), and a secondcompound corresponding in structure to Formula (II-b).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-c), and a secondcompound corresponding in structure to Formula (II-b).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-d), and a secondcompound corresponding in structure to Formula (II-b).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-e), and a secondcompound corresponding in structure to Formula (II-b).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-f), and a secondcompound corresponding in structure to Formula (II-b).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-a), and a secondcompound corresponding in structure to Formula (II-c).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-b), and a secondcompound corresponding in structure to Formula (II-c).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-c), and a secondcompound corresponding in structure to Formula (II-c).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-d), and a secondcompound corresponding in structure to Formula (II-c).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-e), and a secondcompound corresponding in structure to Formula (II-c).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-f), and a secondcompound corresponding in structure to Formula (II-c).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-a), and a secondcompound corresponding in structure to Formula (II-d).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-b), and a secondcompound corresponding in structure to Formula (II-d).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-c), and a secondcompound corresponding in structure to Formula (II-d).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-d), and a secondcompound corresponding in structure to Formula (II-d).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-e), and a secondcompound corresponding in structure to Formula (II-d).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-f), and a secondcompound corresponding in structure to Formula (II-d).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-a), and a secondcompound corresponding in structure to Formula (II-e).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-b), and a secondcompound corresponding in structure to Formula (II-e).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-c), and a secondcompound corresponding in structure to Formula (II-e).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-d), and a secondcompound corresponding in structure to Formula (II-e).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-e), and a secondcompound corresponding in structure to Formula (II-e).

In another embodiment, the composition administered comprises a firstcompound corresponding in structure to Formula (I-f), and a secondcompound corresponding in structure to Formula (II-e).

D. Conditions Treated

In one embodiment, the condition treated by administering thepharmaceutical composition is Parkinson's disease.

In another embodiment, the condition treated by administering thepharmaceutical composition is sleep disturbance in a patient withParkinson's disease (i.e., a method of reducing sleep disturbance in apatient with Parkinson's disease).

In another embodiment, the condition treated by administering thepharmaceutical composition is impaired motor performance in a patientwith Parkinson's disease (i.e., a method of improving motor performancein a patient with Parkinson's disease).

In another embodiment, the pharmaceutical composition is administered totreat motor fluctuations in a patient with Parkinson's disease.

In another embodiment, the pharmaceutical composition is administered totreat dyskinesia in a patient with Parkinson's disease.

In another embodiment, the pharmaceutical composition is administered todelay the onset of motor fluctuations in a patient with Parkinson'sdisease.

In another embodiment, the pharmaceutical composition is administered todelay the onset of dyskinesia in a patient with Parkinson's disease.

In another embodiment, the condition treated by administering thepharmaceutical composition is nighttime disability in a patient withParkinson's disease (i.e., a method of reducing nighttime disabilitiesin a patient with Parkinson's disease).

E. Weight Ratios and Administration Routes

In general, the weight ratio of the first compound (e.g., the phosphateprodrugs) and the second compound (e.g., the phosphate prodrugs)administered to the patient (either separately or together in a singlepharmaceutical composition) is from about 1:1 to about 1:50. In oneaspect, the weight ratio is from about 1:2 to about 1:15. In anotheraspect, the weight ratio is from about 1:4 to about 1:10. In anotheraspect, the weight ratio is about 1:4. In another aspect, the weightratio is about 1:7.5. In another aspect, the weight ratio is about 1:10.

In one embodiment, the first compound (e.g., the phosphate prodrugs) andthe second compound (e.g., the phosphate prodrugs) are administered tothe patient in the form of a solid composition (or solid compositions).In one aspect, the composition is suitable for oral administration.

In one embodiment, the first compound (e.g., the phosphate prodrugs) andthe second compound (e.g., the phosphate prodrugs) are administered tothe patient in the form of a liquid composition (or liquidcompositions). In one aspect, the composition comprises water and issuitable for infusion.

In another embodiment, the first compound (e.g., the phosphate prodrugs)and the second compound (e.g., the phosphate prodrugs) are administeredto the patient as a liquid composition (either separately or in the samepharmaceutical composition) that is suitable for intragastric,subcutaneous, intranasal, intramuscular or intravenous administration.In one aspect, the liquid composition(s) is suitable for intragastricadministration. In another aspect, the liquid composition(s) is suitablefor subcutaneous administration. In another aspect, the liquidcomposition(s) is suitable for intramuscular administration. In anotheraspect, the liquid composition(s) is suitable for intravenousadministration. In another aspect, the liquid composition(s) is suitablefor intranasal administration.

In another embodiment, the first compound (e.g., the phosphate prodrugs)and the second compound (e.g., the phosphate prodrugs) are administeredvia intestinal administration (e.g., intrajejunum, intraduodenum)(either separately or in the same pharmaceutical composition). They canbe administered (or “infused”) directly into the intestine, e.g.,duodenum or the jejunum by a permanent tube inserted via percutaneousendoscopic gastrostomy, for example, with an outer transabdominal tubeand an inner intestinal tube. In one aspect, the first compound (e.g.,the phosphate prodrugs) and the second compound (e.g., the phosphateprodrugs) are administered via a tube inserted by radiologicalgastrojejunostomy. In another aspect, the first compound (e.g., thephosphate prodrugs) and the second compound (e.g., the phosphateprodrugs) are administered via a temporary nasoduodenal tube that isinserted into the patient initially to determine if the patient respondsfavorably to the treatment method before the permanent tube is inserted.

In some embodiments where the first compound (e.g., the phosphateprodrugs) and the second compound (e.g., the phosphate prodrugs) areadministered via intestinal administration, administration can becarried out using a portable pump, such as the pump sold under the tradename, CADD-Legacy Duodopa® Pump®. Specifically, a cassette, pouch, orvial comprising the first compound (e.g., the phosphate prodrugs) andthe second compound (e.g., the phosphate prodrugs) can be attached tothe pump to create the delivery system. The delivery system is thenconnected to the nasoduodenal tube, the transabdominal port, theduodenal tube, or the jejunum tube for intestinal administration.

In one embodiment, the method comprises administering the first compound(e.g., the phosphate prodrugs) and the second compound (e.g., thephosphate prodrugs) (either together or separately) to the patientsubstantially continuously over a period of at least about 12 hours. Inadditional aspects, the first compound (e.g., the phosphate prodrugs)and the second compound (e.g., the phosphate prodrugs) are administeredsubstantially continuously over a period of at least about 16 hours, atleast about 24 hours, about 2 days, about 3 days, about 4 days, about 5days, about 6 days, about one week, or longer. In particular, the firstcompound (e.g., the phosphate prodrugs) and the second compound (e.g.,the phosphate prodrugs) may be subcutaneously administered substantiallycontinuously over a period of at least about 16 hours.

F. Dosing and Plasma Concentrations

In one embodiment, the dosing of the first compound (e.g., the phosphateprodrugs) and the second compound (e.g., the phosphate prodrugs)administered to the patient is adjusted to optimize the clinicalresponse achieved by a subject (e.g. patient), which means maximizingthe functional ON-time during the day by minimizing the number andduration of OFF-time episodes (i.e., bradykinesia) and minimizingON-time with disabling dyskinesia.

In one embodiment, the daily dose of the L-dopa prodrug (i.e., thesecond compound) administered to the patient according to methods of thepresent disclosure may be, for example, about 20 to about 1000000 mg,about 20 to about 100000 mg, about 20 to about 10000 mg, about 20 toabout 5000 mg, about 20 mg to about 4000 mg, about 20 mg to about 3000mg, about 20 mg to about 2000 mg, or about 20 mg to about 1000 mg perday. In particular, L-dopa phosphate prodrug, more particularly L-dopa3′-monophosphate prodrug, L-dopa 4′-monophosphate prodrug and/or L-dopa3′,4′-diphosphate prodrug are administered in the above daily doses.

In one embodiment, the daily dose of the carbidopa prodrug (i.e., thefirst compound) administered to the patient according to methods of thepresent disclosure may be, for example, 0 mg to about 2500 mg, 0 mg toabout 1250 mg, 0 mg to about 1000 mg, 0 mg to about 750 mg, 0 mg toabout 625 mg, 0 mg to about 500 mg, 0 mg to about 375 mg, 0 mg to about250 mg, or 5 mg to about 125 mg per day. In particular, carbidopaphosphate prodrug, more particularly carbidopa 3′-monophosphate prodrug,carbidopa 4′-monophosphate prodrug and/or carbidopa 3′,4′-diphosphateprodrug are administered in the above daily doses.

In some embodiments, an amount of the first compound and an amount ofthe second compound are administered such that in combination they aresufficient to achieve an L-dopa plasma level in the patient of at leastabout 100 ng/mL. In one aspect, the L-dopa plasma level is at leastabout 200 ng/mL. In another aspect, the L-dopa plasma level is at leastabout 300 ng/mL. In another aspect, the L-dopa plasma level is at leastabout 400 ng/mL. In another aspect, the L-dopa plasma level is at leastabout 500 ng/mL. In another aspect, the L-dopa plasma level is at leastabout 600 ng/mL. In another aspect, the L-dopa plasma level is at leastabout 700 ng/mL. In another aspect, the L-dopa plasma level is at leastabout 800 ng/mL. In another aspect, the L-dopa plasma level is at leastabout 900 ng/mL. In another aspect, the L-dopa plasma level is at leastabout 1,000 ng/mL. In another aspect, the L-dopa plasma level is atleast about 1,500 ng/mL. In another aspect, the L-dopa plasma level isat least about 2,000 ng/mL. In another aspect, the L-dopa plasma levelis at least about 3,000 ng/mL. In another aspect, the L-dopa plasmalevel is at least about 4,000 ng/mL. In another aspect, the L-dopaplasma level is at least about 5,000 ng/mL. In another aspect, theL-dopa plasma level is at least about 6,000 ng/mL. In another aspect,the L-dopa plasma level is at least about 7,000 ng/mL. In anotheraspect, the L-dopa plasma level is at least about 8,000 ng/mL. Inanother aspect, the L-dopa plasma level is at least about 9,000 ng/mL.In particular, the first compound may be carbidopa phosphate prodrug,more particularly carbidopa 3′-monophosphate prodrug, carbidopa4′-monophosphate prodrug and/or carbidopa 3′,4′-diphosphate prodrug. Inparticular, the second compound may be L-dopa phosphate prodrug, moreparticularly L-dopa 3′-monophosphate prodrug, L-dopa 4′-monophosphateprodrug and/or L-dopa 3′,4′-diphosphate prodrug.

In some embodiments, an amount of the first compound and an amount ofthe second compound are administered such that in combination they aresufficient to achieve an L-dopa plasma level from about 10 ng/mL toabout 9,000 ng/mL. In one aspect, the L-dopa plasma level is from about10 ng/mL to about 8,000 ng/mL In another aspect, the L-dopa plasma levelis from about 25 ng/mL to about 6,000 ng/mL. In another aspect, theL-dopa plasma level is from about 50 ng/mL to about 4,000 ng/mL. Inanother aspect, the L-dopa plasma level is from about 100 ng/mL to about2,000 ng/mL. In another aspect, the L-dopa plasma level is from about 25ng/mL to about 1,200 ng/mL. In another aspect, the L-dopa plasma levelis from about 10 ng/mL to about 500 ng/mL. In another aspect, the L-dopaplasma level is from about 25 ng/mL to about 500 ng/mL. In particular,the first compound may be carbidopa phosphate prodrug, more particularlycarbidopa 3′-monophosphate prodrug, carbidopa 4′-monophosphate prodrugand/or carbidopa 3′,4′-diphosphate prodrug. In particular, the secondcompound may be L-dopa phosphate prodrug, more particularly L-dopa3′-monophosphate prodrug, L-dopa 4′-monophosphate prodrug and/or L-dopa3′,4′-diphosphate prodrug.

In some embodiments, the above-described L-dopa concentration ranges canbe maintained for at least about a 1 hour interval, a 2 hour interval, a3 hour interval, a 4 hour interval, a 5 hour interval, a 6 hourinterval, a 7 hour interval, an 8 hour interval, a 9 hour interval, a 10hour interval, an 11 hour interval, a 12 hour interval, a 13 hourinterval, a 14 hour interval, a 15 hour interval, a 16 hour interval, a17 hour interval, an 18 hour interval, a 19 hour interval, a 20 hourinterval, a 21 hour interval, a 22 hour interval, a 23 hour interval, ora 24 hour interval.

G. Blood Plasma Levels of L-Dopa Phosphate Prodrug and CarbidopaPhosphate Prodrug.

It has been discovered that in some embodiments, followingadministration of the first compound and the second compound, anunexpected concentration of the second compound, i.e., an L-dopaphosphate prodrug, remains in the blood plasma and does not convert toL-dopa. Additionally, there may be an unexpected concentration of thefirst compound, i.e., a carbidopa phosphate prodrug, which remains inthe blood plasma and does not convert to carbidopa. Surprisingly, theL-dopa phosphate prodrug and/or the carbidopa phosphate prodrug mayremain in blood plasma during full duration of continuous infusion ofthe first compound and/or second compound.

Therefore in some embodiments, administration of the first and secondcompound results in an L-dopa phosphate prodrug plasma level from about0 ng/mL to about 3600 ng/mL, about 1 ng/mL to about 3600 ng/mL, or about10 ng/mL to about 3600 ng/mL. In one aspect, the L-dopa phosphateprodrug plasma level is from about 10 ng/mL to about 3200 ng/mL. Inanother aspect, the L-dopa phosphate prodrug plasma level is from about25 ng/mL to about 2800 ng/mL. In another aspect, the L-dopa phosphateprodrug plasma level is from about 50 ng/mL to about 2400 ng/mL. Inanother aspect, the L-dopa phosphate prodrug plasma level is from about10 ng/mL to about 2000 ng/mL. In another aspect, the L-dopa phosphateprodrug plasma level is from about 25 ng/mL to about 1600 ng/mL. Inanother aspect, the L-dopa phosphate prodrug plasma level is from about25 ng/mL to about 1200 ng/mL. In another aspect, the L-dopa phosphateprodrug plasma level is from about 10 ng/mL to about 800 ng/mL. Inanother aspect, the L-dopa phosphate prodrug plasma level is from about10 ng/mL to about 400 ng/mL. In another aspect, the L-dopa phosphateprodrug plasma level is from about 10 ng/mL to about 200 ng/mL. Inanother aspect, the L-dopa phosphate prodrug plasma level is from about10 ng/mL to about 100 ng/mL.

In some embodiments, administration of the first and second compoundresults in an carbidopa phosphate prodrug plasma level from about 0ng/mL to about 600 ng/mL, about 1 ng/mL to about 600 ng/mL or about 10ng/mL to 600 ng/mL. In one aspect, the carbidopa phosphate prodrugplasma level is from about 10 ng/mL to about 500 ng/mL. In anotheraspect, the carbidopa phosphate prodrug plasma level is from about 10ng/mL to about 400 ng/mL. In another aspect, the carbidopa phosphateprodrug plasma level is from about 10 ng/mL to about 300 ng/mL. Inanother aspect, the carbidopa phosphate prodrug plasma level is fromabout 10 ng/mL to about 200 ng/mL. In another aspect, the carbidopaphosphate prodrug plasma level is from about 10 ng/mL to about 100ng/mL. In another aspect, the carbidopa phosphate prodrug plasma levelis from about 25 ng/mL to about 600 ng/mL. In another aspect, thecarbidopa phosphate prodrug plasma level is from about 25 ng/mL to about500 ng/mL. In another aspect, the carbidopa phosphate prodrug plasmalevel is from about 25 ng/mL to about 400 ng/mL. In another aspect, thecarbidopa phosphate prodrug plasma level is from about 25 ng/mL to about300 ng/mL. In another aspect, the carbidopa phosphate prodrug plasmalevel is from about 25 ng/mL to about 200 ng/mL. In another aspect, thecarbidopa phosphate prodrug plasma level is from about 25 ng/mL to about100 ng/mL.

L-dopa phosphate prodrug concentration ranges and/or carbidopa phosphateprodrug plasma concentration ranges can be maintained for at least abouta 1 hour interval, a 2 hour interval, a 3 hour interval, a 4 hourinterval, a 5 hour interval, a 6 hour interval, a 7 hour interval, an 8hour interval, a 9 hour interval, a 10 hour interval, an 11 hourinterval, a 12 hour interval, a 13 hour interval, a 14 hour interval, a15 hour interval, a 16 hour interval, a 17 hour interval, an 18 hourinterval, a 19 hour interval, a 20 hour interval, a 21 hour interval, a22 hour interval, a 23 hour interval, or a 24 hour interval. Further,the L-dopa phosphate prodrug concentration ranges and/or carbidopaphosphate prodrug concentration ranges may be maintained at theaforementioned intervals day-after-day, e.g., 2 days, 3 days, 4 days, 5days, 6 days, 7 days, etc. Without being bound by theory, this may aidcontinuous administration of the first and second compound (eithertogether or separately).

In some embodiments, an amount of the first compound and an amount ofthe second compound are administered such that they are sufficient tomaintain a carbidopa plasma level less than about 2500 ng/mL. In oneaspect, the carbidopa plasma level is less than about 2000 ng/mL. Inanother aspect, the carbidopa plasma level is less than about 1500ng/mL. In another aspect, the carbidopa plasma level is less than about1000 ng/mL. In another aspect, the carbidopa plasma level is less thanabout 500 ng/mL. In another aspect, the carbidopa plasma level is lessthan about 250 ng/mL. In another aspect, the carbidopa plasma level isless than about 100 ng/mL. In another aspect, the carbidopa plasma levelis less than about 50 ng/mL. In another aspect, the carbidopa plasmalevel is less than about 25 ng/mL.

In some embodiments, the above-described carbidopa plasma concentrationranges are maintained for at least about: a 1 hour interval, a 2 hourinterval, a 3 hour interval, a 4 hour interval, a 5 hour interval, a 6hour interval, a 7 hour interval, an 8 hour interval, a 9 hour interval,a 10 hour interval, an 11 hour interval, a 12 hour interval, a 13 hourinterval, a 14 hour interval, a 15 hour interval, a 16 hour interval, a17 hour interval, an 18 hour interval, a 19 hour interval, a 20 hourinterval, a 21 hour interval, a 22 hour interval, a 23 hour interval, ora 24 hour interval.

H. Phosphorous Load

In some embodiments, an amount of the first compound and an amount ofthe second compound can be administered to a subject and achieve aphosphorus intake of less than about 2000 mg/day, or less than about2500 mg/day or less than about 3000 mg/day. The value 3000 mg/day is theaccepted tolerable upper intake level. See DRI Dietary Reference Intakesfor Calcium, Phosphorus, Vitamin D and Fluoride atwww.nap.edu/ctalog/5776. In further embodiments, administration oftherapeutic concentrations of the first and the second compound to asubject results in a total phosphorus load of about 350 mg/day to about550 mg/day, or about 400 mg/day to about 500 mg/day, or about 400 mg/dayto about 450 mg/day, or approximately 427 mg/day. The average dietaryphosphorus intake in the U.S. population is approximately 1500 mg/day.See Ervin R. B., et al. 2004. Dietary intake of selected minerals forthe United States population: 1999-2000. Adv Data. April 27; (341):1-5.Thus, the total phosphorus exposure from administration of the first andthe second compound can be about 1850 mg/day to about 2000 mg/day, orabout 1900 mg/day to about 1950 mg/day or about 1927 mg/day, which issignificantly less than the accepted tolerable upper intake level of3000 mg/day.

VI. Co-Administration and/or Add-On Therapy

The methods of treatment of the present disclosure optionally canfurther comprise administration of one or more therapeutic agents forthe treatment of Parkinson's disease (e.g. an anti-Parkinson's agent) inaddition to the L-dopa prodrug and the carbidopa prodrug. In oneembodiment, the additional therapeutic agent(s) is selected from thegroup consisting of decarboxylase inhibitors other than carbidopa (e.g.,benserazide), catechol-O-methyl transferase (“COMT”) inhibitors (e.g.,entacapone and tolcapone), and monoamine oxidase A (“MAO-A”) ormonoamine oxidase B (“MAO-B”) inhibitors (e.g., moclobemide, rasagiline,selegiline, and safinamide). In one aspect, the additional therapeuticagent(s) is selected from the group consisting of decarboxylaseinhibitors other than carbidopa. In another aspect, the additionaltherapeutic agent(s) is selected from the group consisting of COMTinhibitors, such as entacapone. In another aspect, the additionaltherapeutic agent(s) is selected from the group consisting of MAO-Ainhibitors. In another aspect, the additional therapeutic agent(s) isselected from the group consisting of MAO-B inhibitors.

The additional therapeutic agents and the first and second compound canbe administered together or separately; and substantially simultaneouslyor subsequent to each other. Additionally, the additional therapeuticagents and the first and second compound can be in separate dosage formswhich can be the same or different. For example, entacapone can be usedadjunctively and can be orally delivered, and the first and the secondcompound discussed herein can be subcutaneously administered (separatelyor together in the same pharmaceutical composition). Further, thetherapeutic agents and the first and the second compound can optionallybe co-packaged, for example in a single container or in a plurality ofcontainers within a single outer package, or co-presented in separatepackaging (“common presentation”).

In a similar manner, the pharmaceutical compositions of the presentdisclosure optionally can further comprise one or more additionaltherapeutic agents for the treatment of Parkinson's disease as describedabove.

VII. Kits

The present disclosure also relates to kits comprising one or morepharmaceutical dosage forms comprising a carbidopa phosphate prodrug;kits comprising one or more pharmaceutical dosage forms comprising a anL-dopa phosphate prodrug; and kits comprising one or more pharmaceuticaldosage forms comprising both a carbidopa phosphate prodrug and an L-dopaphosphate prodrug. The kit optionally can comprise one or moreadditional therapeutic agents and/or instructions, for example,instructions for using the kit to treat a patient having Parkinson'sdisease and an associated condition.

In one embodiment, the kit comprises a first pharmaceutical dosage form,wherein the first pharmaceutical dosage form comprises a first compoundcorresponding in structure to Formula (I), or a pharmaceuticallyacceptable salt thereof. In one aspect, the kit comprises a secondpharmaceutical dosage form comprising a second compound corresponding instructure to Formula (II), or a pharmaceutically acceptable saltthereof. In another aspect, the first pharmaceutical dosage form furthercomprises a second compound corresponding in structure to Formula (II),or a pharmaceutically acceptable salt thereof. In another aspect, thefirst pharmaceutical dosage form and, where applicable, the secondpharmaceutical dosage form are liquid pharmaceutical dosage forms.

As dopamine is an achiral compound, the various embodiments discussedabove potentially could be adapted for use with a D-dopa phosphateprodrug or a racemate of D-dopa phosphate prodrug and L-dopa phosphateprodrug in place of the L-dopa phosphate prodrug.

VIII. L-Dopa and Carbidopa Prodrug Polymorphs

Particular crystalline forms of the L-dopa prodrugs and carbidopaprodrugs described above also have been identified and are describedherein. More particularly, such crystalline forms are L-dopa4′-monophosphate anhydrate (i), L-dopa 4′-monophosphate anhydrate (ii),L-dopa 3′-monophosphate, L-dopa 3′,4′-diphosphate trihydrate, carbidopa4′-monophosphate trihydrate, carbidopa 4′-monophosphate dihydrate,carbidopa 4′-monophosphate dehydrate, carbidopa 3′-monophosphate (i),carbidopa 3′-monophosphate (ii), and carbidopa 3′,4′-diphosphate sodiumsalt.

A. L-Dopa Prodrug Polymorphs

L-dopa 4′-monophosphate anhydrate (i) crystalline solid can beidentified by characteristic peaks in its powder X-ray diffractionpattern (FIG. 13). One with skill in the art of analytical chemistrywould be able to readily identify L-dopa 4′-monophosphate anhydrate (i)solid by as few as one characteristic peak in its powder X-raydiffraction pattern. Therefore, in one or more embodiments, acrystalline L-dopa 4′-monophosphate anhydrate (i) is provideddemonstrating at least 1, at least 2, at least 3, at least 4, at least5, at least 6, at least 7, at least 8, at least 9, at least 10, at least11, at least 12, at least 13, at least 14 or 15 characteristic peaks ina powder X-ray diffraction pattern at values of two theta of10.261±0.20, 12.053±0.20, 13.759±0.20, 14.932±0.20, 16.147±0.20,16.718±0.20, 17.34±0.20, 19.254±0.20, 20.654±0.20, 22.078±0.20,23.599±0.20, 24.198±0.20, 25.898±0.20, 26.338±0.20, and 27.117±0.20.Crystallographic unit cell parameters of L-dopa 4′-monophosphateanhydrate (i) also were obtained and were determined as: a is 7.0508 Å,b is 10.6253 Å, c is 14.7588 Å, to afford a cell volume of 1105.68 Å³,wherein a, b, and c are each a representative length of the crystallattice.

L-dopa 4′-monophosphate anhydrate (ii) crystalline solid can beidentified by characteristic peaks in its powder X-ray diffractionpattern (FIG. 14). One with skill in the art of analytical chemistrywould be able to readily identify L-dopa 4′-monophosphate anhydrate (ii)solid by as few as one characteristic peak in its powder X-raydiffraction pattern. Therefore, in one or more embodiments, acrystalline L-dopa 4′-monophosphate anhydrate (ii) is provideddemonstrating at least 1, at least 2, at least 3, at least 4, at least5, at least 6, at least 7, at least 8, at least 9, at least 10, at least11, at least 12, at least 13, at least 14 or 15 characteristic peaks ina powder X-ray diffraction pattern at values of two theta of 8.468±0.20,10.234±0.20, 11.821±0.20, 13.084±0.20, 13.503±0.20, 15.48±0.20,15.848±0.20, 16.513±0.20, 18.447±0.20, 19.346±0.20, 20.239±0.20,21.139±0.20, 24.221±0.20, 24.865±0.20, 25.647±0.20.

L-dopa 3′-monophosphate crystalline solid can be identified bycharacteristic peaks in its powder X-ray diffraction pattern (FIG. 15).One with skill in the art of analytical chemistry would be able toreadily identify L-dopa 3′-monophosphate solid by as few as onecharacteristic peak in its powder X-ray diffraction pattern. Therefore,in one or more embodiments, a crystalline L-dopa 3′-monophosphate isprovided demonstrating at least 1, at least 2, at least 3, at least 4,at least 5, at least 6, at least 7, at least 8, at least 9, at least 10,at least 11, at least 12, at least 13, at least 14 or 15 characteristicpeaks in a powder X-ray diffraction pattern at values of two theta of8.662±0.20, 11.286±0.20, 15.079±0.20, 15.678±0.20, 16.786±0.20,17.288±0.20, 18.438±0.20, 19.682±0.20, 20.946±0.20, 22.188±0.20,22.671±0.20, 23.088±0.20, 24.144±0.20, 24.744±0.20, and 25.383±0.20.

L-dopa 3′,4′-diphosphate trihydrate crystalline solid can be identifiedby characteristic peaks in its powder X-ray diffraction pattern (FIG.16). One with skill in the art of analytical chemistry would be able toreadily identify L-dopa 3′,4′-diphosphate trihydrate solid by as few asone characteristic peak in its powder X-ray diffraction pattern.Therefore, in one or more embodiments, a crystalline L-dopa3′,4′-diphosphate trihydrate is provided demonstrating at least 1, atleast 2, at least 3, at least 4, at least 5, at least 6, at least 7, atleast 8, at least 9, at least 10, at least 11, at least 12, at least 13,at least 14 or 15 characteristic peaks in a powder X-ray diffractionpattern at values of two theta of 7.118±0.20, 10.342±0.20, 11.355±0.20,12.161±0.20, 14.201±0.20, 17.36±0.20, 17.632±0.20, 19.196±0.20,19.444±0.20, 20.83±0.20, 21.504±0.20, 22.491±0.20, 23.085±0.20,24.487±0.20, and 25.11±0.20.

B. Carbidopa Prodrug Polymorphs

Carbidopa 4′-monophosphate trihydrate crystalline solid can beidentified by characteristic peaks in its powder X-ray diffractionpattern (FIG. 17). One with skill in the art of analytical chemistrywould be able to readily identify carbidopa 4′-monophosphate trihydratesolid by as few as one characteristic peak in its powder X-raydiffraction pattern. Therefore, in one or more embodiments, acrystalline carbidopa 4′-monophosphate trihydrate is provideddemonstrating at least 1, at least 2, at least 3, at least 4, at least5, at least 6, at least 7, at least 8, at least 9, at least 10, at least11, at least 12, at least 13, at least 14 or 15 characteristic peaks ina powder X-ray diffraction pattern at values of two theta of 7.484±0.20,10.05±0.20, 11.971±0.20, 13.085±0.20, 14.923±0.20, 16.095±0.20,16.85±0.20, 17.359±0.20, 17.635±0.20, 19.269±0.20, 19.544±0.20,21.842±0.20, 22.578±0.20, 22.921±0.20, and 23.822±0.20.

Crystallographic unit cell parameters of carbidopa 4′-monophosphatetrihydrate also were obtained and were determined as: a is 7.0226 Å, bis 9.4565 Å, c is 23.615 Å, to afford a cell volume of 1568.25 Å³,wherein a, b, and c are each a representative length of the crystallattice.

Carbidopa 4′-monophosphate dihydrate crystalline solid can be identifiedby characteristic peaks in its powder X-ray diffraction pattern (FIG.18). One with skill in the art of analytical chemistry would be able toreadily identify carbidopa 4′-monophosphate dihydrate solid by as few asone characteristic peak in its powder X-ray diffraction pattern.Therefore, in one or more embodiments, a crystalline carbidopa4′-monophosphate dihydrate is provided demonstrating at least 1, atleast 2, at least 3, at least 4, at least 5, at least 6, at least 7, atleast 8, at least 9, at least 10, at least 11, at least 12, at least 13,at least 14 or 15 characteristic peaks in a powder X-ray diffractionpattern at values of two theta of 7.925±0.20, 10.28±0.20, 12.344±0.20,15.002±0.20, 15.841±0.20, 16.158±0.20, 17.565±0.20, 18.506±0.20,19.058±0.20, 19.473±0.20, 19.702±0.20, 20.188±0.20, 20.668±0.20,22.37±0.20, and 24.167±0.20.

Carbidopa 4′-monophosphate dehydrate crystalline solid can be identifiedby characteristic peaks in its powder X-ray diffraction pattern (FIG.19). One with skill in the art of analytical chemistry would be able toreadily identify carbidopa 4′-monophosphate dehydrate solid by as few asone characteristic peak in its powder X-ray diffraction pattern.Therefore, in one or more embodiments, a crystalline carbidopa4′-monophosphate dehydrate is provided demonstrating at least 1, atleast 2, at least 3, at least 4, at least 5, at least 6, at least 7, atleast 8, at least 9, or at least 10 characteristic peaks in a powderX-ray diffraction pattern at values of two theta of 9.492±0.20,10.528±0.20, 15.356±0.20, 15.907±0.20, 16.165±0.20, 17.933±0.20,18.737±0.20, 19.429±0.20, 21.176±0.20, and 22.626±0.20.

Carbidopa 3′-monophosphate (i) crystalline solid can be identified bycharacteristic peaks in its powder X-ray diffraction pattern (FIG. 20).One with skill in the art of analytical chemistry would be able toreadily identify carbidopa 3′-monophosphate (i) solid by as few as onecharacteristic peak in its powder X-ray diffraction pattern. Therefore,in one or more embodiments, a crystalline carbidopa 3′-monophosphate (i)is provided demonstrating at least 1, at least 2, at least 3, at least4, at least 5, at least 6, at least 7, at least 8, at least 9, or atleast 10 characteristic peaks in a powder X-ray diffraction pattern atvalues of two theta of 9.171±0.20, 13.539±0.20, 14.23±0.20, 15.589±0.20,15.979±0.20, 18.394±0.20, 18.832±0.20, 19.315±0.20, 22.143±0.20, and22.81±0.20.

Carbidopa 3′-monophosphate (ii) crystalline solid can be identified bycharacteristic peaks in its powder X-ray diffraction pattern (FIG. 21).One with skill in the art of analytical chemistry would be able toreadily identify carbidopa 3′-monophosphate (ii) solid by as few as onecharacteristic peak in its powder X-ray diffraction pattern. Therefore,in one or more embodiments, a crystalline carbidopa 3′-monophosphate(ii) is provided demonstrating at least 1, at least 2, at least 3, atleast 4, at least 5, at least 6, at least 7, at least 8, at least 9, orat least 10 characteristic peaks in a powder X-ray diffraction patternat values of two theta of 4.433±0.20, 8.917±0.20, 9.654±0.20,13.192±0.20, 15.288±0.20, 15.747±0.20, 17.886±0.20, 19.291±0.20,20.554±0.20, and 21.797.

Carbidopa 3′,4′-diphosphate sodium salt crystalline solid can beidentified by characteristic peaks in its powder X-ray diffractionpattern (FIG. 22). One with skill in the art of analytical chemistrywould be able to readily identify carbidopa 3′,4′-diphosphate sodiumsalt solid by as few as one characteristic peak in its powder X-raydiffraction pattern. Therefore, in one or more embodiments, acrystalline carbidopa 3′,4′-diphosphate sodium salt is provideddemonstrating at least 1, at least 2, at least 3, at least 4, at least5, at least 6, at least 7, at least 8, at least 9, at least 10, at least11, at least 12, at least 13, at least 14 or 15 characteristic peaks ina powder X-ray diffraction pattern at values of two theta of 5.852±0.20,6.861±0.20, 7.338±0.20, 11.159±0.20, 11.729±0.20, 12.953±0.20,13.714±0.20, 14.381±0.20, 14.686±0.20, 15.479±0.20, 16.676±0.20,17.179±0.20, 17.592±0.20, 18.861±0.20 and 20.305±0.20.

Compositions and combinations comprising the above-described L-dopa andcarbidopa polymorphs are also contemplated. Therefore, in one or moreembodiments, pharmaceutical compositions and combinations comprising theabove-described L-dopa and carbidopa polymorphs are provided as well asmethods of treating Parkinson's disease by administering suchpharmaceutical compositions and combinations. In particular methods oftreating Parkinson's disease by administering a pharmaceuticalcomposition comprising one or more of the L-dopa and carbidopapolymorphs identified by characteristic peaks in the powder X-raydiffraction patterns of any one of FIGS. 13-22 is provided.

Powder X-ray diffraction (PXRD) analysis of samples was conducted in thefollowing manner. Samples for X-ray diffraction analysis were preparedby spreading the sample in a thin layer on the sample holder and gentlyflattening the sample with a microscope slide. For example, the samplemay have been ground to a fine powder with mortar and pestle, or withglass microscope slides for limited quantity samples. Samples were runin one of three configurations: circular bulk holder, a quartz zerobackground plate, or hot stage mount (similar mounting to a zerobackground plate).

Diffraction patterns were collected using an Inel G3000 difrractometerequipped with an incident beam germanium monochromator to provideCu-K_(α1) radiation. The X-ray generator was operated at a voltage of 40kV and a current of 30 mA. The Inel G3000 is equipped with a positionsensitive detector that monitors all diffraction data simultaneously.The detector was calibrated by collecting the attenuated direct beam forseven seconds in 1 degree intervals across a 90 degree two theta range.The calibration was checked against a silicon line position referencestandard (NIST 640c). Samples were placed on an aluminum sample holderand leveled with a glass slide.

Alternatively, X-ray powder diffraction can be performed using a RigakuMiniflex difractometer (30 kV and 15 mA; X-ray source: Cu; Range:2.00-40.00° Two Theta; Scan rate: 1-5 degree/minute) or a Scintag X1 orX2 difractometer (2 kW normal focus X-ray tube with either a liquidnitrogen or Peltier cooled germanium solid state detector; 45 kV and 40mA; X-ray source: Cu; Range: 2.00-40.00° Two Theta; Scan Rate: 1-5degree/minute).

Characteristic powder X-ray diffraction pattern peak positions arereported in terms of angular positions (two theta) with an allowablevariability of ±0.20°. The variability of ±0.10° is intended to be usedwhen comparing two powder X-ray diffraction patterns. In practice, if adiffraction pattern peak from one pattern is assigned a range of angularpositions (two theta) which is the measured peak position ±0.20° and adiffraction pattern peak from another pattern is assigned a range ofangular positions (two theta) which is measured peak position ±0.20° andif those ranges of peak position overlap, then the two peaks areconsidered to have the same angular position (two theta). For example,if a diffraction pattern peak from one pattern is determined to have apeak position of 5.20° for comparison purposes the allowable variabilityallows the peak to be assigned a position in the range of 5.00°-5.40°.If a comparison peak from the other diffraction pattern is determined tohave a peak position of 5.35° and the allowable variability allows thepeak to be assigned a position in the range of 5.15°-5.55°, then the twopeaks being compared are considered to have the same angular position(two theta) because there is overlap between the two ranges of peakpositions.

Single crystal X-ray diffraction analysis of samples was conducted inthe following manner. Samples for X-ray diffraction analysis wereprepared by affixing selected single crystals to glass pins with epoxyadhesive. X-ray diffraction data was collected using a Bruker SMARTsystem with an APEX area detector (50 kv and 40 mA; X-ray source: Mo).Data were collected at −100° C.

IX. Examples

The following non-limiting examples are provided to further illustratethe present disclosure. Abbreviations used in the examples below includethe following:

-   -   “DBU” means 1,8-diazabicyclo[5.4.0]-undec-7-ene.    -   “DCM” means dichloromethane.    -   “EDTA” means ethylenediaminetetraacetic acid.    -   “FCC” means flash column chromatography.    -   “HPLC” means high pressure liquid chromatography    -   “IPA” means isopropanol.    -   “LC-MS” means liquid chromatography-mass spectrometry.    -   “m-CPBA” means meta-chloroperoxybenzoic acid.    -   “MTBE” means methyl tertiary butyl ether.    -   “pa” means peak area.    -   “THF” means tetrahydrofuran.    -   “TLC” means thin layer chromatography.    -   “t_(1/2)” means biological half-life, i.e., the time required        for half the quantity of a drug or other substance administered        to a living organism to be metabolized or eliminated by normal        biological processes.

Example 1 Synthesis of L-Dopa Monophosphates

L-dopa 3′-monophosphate and L-dopa 4′-monophosphate were prepared asshown in Scheme 1 below:

Specifically, L-dopa 3′-monophosphate and L-dopa 4′-monophosphate wereprepared as described in Steps 1 through 5B below.

Step 1

A solution of sodium hydroxide (40 g, 1.0 mol) in water (300 mL) wasadded drop-wise to a suspension of Compound 1 (100 g, 0.5 mol) in water(300 mL) over a period of 20 minutes at 0° C. Benzylchloroformate (103.9g, 0.6 mol) in dioxane (400 mL) was added drop-wise to the suspensionover a period of 30 minutes at 0° C. and then the reaction mass wasstirred at room temperature for 16 hours. Reaction completion wasmonitored by TLC. After the complete consumption of starting material,the reaction mass was basified to pH=10 using 10% sodium hydroxide (200mL) and extracted with MTBE (500 mL). The organic layer was separatedand discarded. The aqueous layer was acidified to pH=2 using 6 N HCl(150 mL) and extracted with MTBE (500 mL×2). The combined organic layerwas washed with water (500 mL), saturated sodium chloride solution (500mL), dried over sodium sulfate, and concentrated under vacuum at 45° C.to 50° C. to provide crude Compound 2 as a viscous liquid (120 g, 72%).

Step 2

Cesium carbonate (123 g, 0.37 mol) was added in two lots to a solutionof Compound 2 (250 g, 0.75 mol) in dimethylformamide (2 L) at 0° C.Benzyl bromide (90.3 mL, 0.75 mol) was added drop-wise to this mixtureover a period of 30 minutes at 0° C. and then the reaction mass wasstirred at room temperature for 16 hours. Reaction completion wasmonitored by TLC. After the complete consumption of starting material,the reaction mass was diluted with water (5 L) and extracted with MTBE(1 L×2). The combined organic layer was washed with water (1 L),saturated sodium chloride solution (0.5 L), dried over sodium sulfate,and concentrated under vacuum at 45° C. to 50° C. to provide crudeCompound 4 as a viscous liquid (250 g).

Step 3

Cesium carbonate (698.5 g, 2.14 mol) was added in four lots to asolution of Compound 3 (900 g, 2.14 mol) in dimethylformamide (7.2 L) at0° C. Benzyl bromide (512 mL, 4.28 mol) was added drop-wise to thismixture over a period of one hour at 0° C. and then the reaction masswas stirred at room temperature for 16 hours. Reaction completion wasmonitored by TLC. After the complete consumption of starting material,the reaction mass was diluted with water (15 L) and extracted with MTBE(3 L×2). The combined organic layer was washed with water (3 L),saturated sodium chloride solution (1.5 L), dried over sodium sulfate,and concentrated under vacuum at 45° C. to 50° C. to provide a crudeproduct as a viscous liquid (1 Kg).

The crude product obtained was blended with the crude product fromprevious batches (total of 1.6 Kg) and was repeatedly purified by flashcolumn chromatography over silica gel (230-400 mesh) using 10-20% ethylacetate in petroleum ether to provide Compounds 4a (270 g) and 4b (255g).

Step 4A

Potassium tert-butoxide (65.6 g, 0.58 mol) was added in four lots to asolution of Compound 4a (200 g, 0.39 mol) in tetrahydrofuran (2.0 L) at0° C. A 10% w/w solution dibenzylphosphoryl chloride in toluene (2.31Kg, 0.78 mol) was added drop-wise to this mixture over a period of 30minutes at 0° C. and then the reaction mass was stirred at roomtemperature for 2 hours. Reaction completion was monitored by thin layerchromatography. After the complete consumption of starting material, thereaction mass was cooled to 0° C. to 5° C. and quenched with water (1.0L). The organic layer was separated and the aqueous layer was extractedwith toluene (500 mL). The combined organic layer was washed with water(1 L), saturated NaCl solution (500 mL), dried over sodium sulfate, andconcentrated under vacuum at 45° C. to 50° C. The crude product obtainedwas purified by column chromatography over silica gel (230-400 mesh)using 30%-40% ethyl acetate in petroleum ether to yield Compound 5a as aviscous liquid (185 g, 61.6%).

Step 4B

Potassium tert-butoxide (68.9 g, 0.61 mol) was added in four lots to asolution of Compound 4b (210 g, 0.41 mol) in tetrahydrofuran (2.2 L) at0° C. A 10% w/w solution dibenzylphosphoryl chloride in toluene (2.43Kg, 0.82 mol) was added drop-wise to this mixture over a period of 30minutes at 0° C. After complete addition, the reaction mass was stirredat room temperature for 2 hours. Reaction completion was monitored bythin layer chromatography. After reaction completion, the reaction masswas cooled to 0° C. to 5° C. and quenched with water (1.0 L). Theorganic layer was separated and the aqueous layer was extracted withtoluene (500 mL). The combined organic layer was washed with water (1L), saturated NaCl solution (500 mL), dried over sodium sulfate, andconcentrated under vacuum at 45° C. to 50° C. The crude product obtainedfrom this batch was blended with the crude product (45 g) from anotherbatch and purified by column chromatography over silica gel (230-400mesh) using 30%-40% ethyl acetate in petroleum ether to yield Compound5b as a viscous liquid (250 g, 65%).

Step 5A

10% Pd/C (30 g, 50% wet) was added to a solution of Compound 5a (100 g,0.13 mol) in ethanol and water (1 L, 4:1) under nitrogen atmosphere. Thereaction flask was evacuated and purged with hydrogen gas three timesand then hydrogenated at 4 Kg/cm² pressure (approximately 4 atmospheres)for 16 hours. After the reaction was complete, water (500 mL) was addedto the reaction mixture and the catalyst was removed by filtrationthrough K100 cellulose filter pad (520 mm diameter). The filtrate wasconcentrated under reduced pressure. The crude product obtained wasstirred with ethanol (60 mL), filtered, and dried under suction to give(S-2-amino-3-(3-hydroxy-4-(phosphonooxy)phenyl)-propanoic acid; L-dopa(4-phosphate) (17 g, 47%) as an off-white solid. ¹H NMR (300 MHz, D₂O) δ7.1 (d, J=8.1 Hz, 1H), 6.7 (s, 1H), 6.68 (d, J=8.1 Hz, 1H), 4.1 (q,J=5.1 Hz, 1H), 3.15 (dd, J=14.7 Hz, 4.5 Hz, 1H), 3.0-2.93 (m, 1H); MS(LCMS) m/z 278 [M+H]+.

Step 5B

10% Pd/C (30 g, 50% wet) was added to a solution of Compound 5b (100 g,0.13 mol) in ethanol and water (1 L, 4:1) under nitrogen atmosphere. Thereaction flask was evacuated and purged with hydrogen gas three timesand then hydrogenated at 4 Kg/cm² pressure (approximately 4 atmospheres)for 16 hours. After the reaction was complete, water (500 mL) was addedto the reaction mixture and the catalyst was removed by filtrationthrough K100 cellulose filter pad (520 mm diameter). The filtrate wasconcentrated under reduced pressure. The crude product obtained wasstirred with ethanol (60 mL), filtered, and dried under suction to give(S-2-amino-3-(4-hydroxy-3-(phosphonooxy)phenyl)-propanoic acid; L-dopa(3-phosphate) (21 g, 58.5%) as an off-white solid. ¹H NMR (300 MHz, D₂O)δ 7.06 (s, 1H), 6.85 (s, 2H), 4.08 (q, J=4.8 Hz, 1H), 3.16 (dd, J=14.7Hz, 5.1 Hz, 1H), 3.0-2.92 (m, 1H); MS (LCMS) m/z 278 [M+H]+.

Example 2 Synthesis of L-Dopa Diphosphate

L-dopa 3′,4′-diphosphate was prepared as shown in Scheme 2 below:

Specifically, L-dopa 3′,4′-diphosphate was prepared as described inSteps 6 and 7 below.

Step 6

Cesium carbonate (484 g, 1.48 mol) was added in two lots to a solutionof Compound 3 (250 g, 0.59 mol) in dimethylformamide (2.5 L) at 0° C. A10% w/w solution of dibenzylphosphoryl chloride in toluene (3.52 Kg,1.18 mol) was added drop-wise to this mixture over a period of one hourat 0° C. and then the reaction mass was stirred at room temperature for2 hours. Reaction completion was monitored by TLC. After the completeconsumption of the starting material, the reaction mass was cooled to 0°C. to 5° C. and quenched with water (5 L). The organic layer wasseparated and the aqueous layer was extracted with toluene (1 L). Thecombined organic layer was washed with water (1 L), saturated sodiumchloride solution (0.5 L), dried over sodium sulfate, filtered, andconcentrated under vacuum at 45° C. to 50° C. The crude product obtainedwas purified by column chromatography over silica gel (230-400 mesh)using 10%-15% ethyl acetate in petroleum ether to provide Compound 6 asa gummy liquid (240 g) of intermediate purity.

Step 7

10% Pd/C (20 g, 50% wet) was added to a solution of Compound 6 (50 g,0.05 mol) in THF (500 mL) under nitrogen atmosphere. The reaction flaskwas evacuated and purged with hydrogen gas three times and thenhydrogenated at 6 Kg/cm² pressure for 8 hours. After the reaction wascomplete, water (250 mL) was added to the reaction mixture and thecatalyst was removed by filtration through K100 cellulose filter pad(520 mm diameter). The filtrate was concentrated under reduced pressure.The crude product obtained was stirred with ethanol (30 mL), filtered,and dried under suction to provide L-dopa (3,4-Phosphate) (12.8 g, 64%,purity corrected) as off-white solid. ¹H NMR (300 MHz, D₂O) δ 7.21 (d,J=8.4 Hz, 1H), 7.16 (s, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.23 (q, J=2.7 Hz,1H), 3.24 (dd, J=15 Hz, 4.8 Hz, 1H), 3.08-3.01 (m, 1H); MS (LCMS) m/z358 [M+H]+.

Example 3 Synthesis of Carbidopa Monophosphates

Carbidopa 3′-phosphate and carbidopa 4′-phosphate were prepared as shownin Scheme 3 below:

Specifically, carbidopa 3′-phosphate and carbidopa 4′-phosphate wereprepared as described in Step 1 below.

Step 1

A thick mixture of phosphorus pentoxide (2.325 g, 16.38 mmol) andphosphoric acid (85% aq., 1.79 mL, 26.2 mmol) was heated to 100° C. for15 minutes resulting in a clear solution. The solution was cooled backto 50° C. and carbidopa monohydrate (0.400 g, 1.64 mmol) was added.After 3 hours, the solution was cooled to room temperature, stirred for14 hours, and then warmed to 35° C. After 24 hours, the solution wascooled to room temperature and stirred for 60 hours. Water (2 mL,exotherm to 50° C.) was added, the solution was stirred for 5 minutes,and then analyzed by HPLC (Agilent Poroshell 120 EC-C18 #693975-9024.6×150 mm column, 1 mL/minute 0.1% aq. H₃PO₄/CH₃CN, 3 minute 97:3, 4minute gradient to 70:30, 2 minute gradient to 0:100, hold 1 minute,detection at 220 nm) showing: carbidopa (6.7 minutes): 2.6 pa %,phosphate 1 (5.1 minutes): 38.2 pa %, phosphate 2 (5.7 minutes): 37.7 pa%, diphosphate (2.3 minutes): 5.9 pa %. The aqueous solution was dilutedwith water (5×), then purified by preparative HPLC (Kromasil Phenyl 3 cmID×25 cm, 5 micron column, 30 mL/minute 0.1% formic acid/CH₃CN, 10minute 97:3, 5 minute gradient to 93:7, 0.5 minute gradient to 100:0,detection at 277 nm). Pure fractions of separated monophosphates werecombined, concentrated on a rotary evaporator (35° C. bath temperature)to 10 mL each, then lyophilized, giving carbidopa 4′-phosphate 1 (152mg, 30% yield) and carbidopa 3′-phosphate 2 (137 mg, 27% yield) as whiteamorphous powders. Carbidopa 3′-monophosphate: ¹H NMR (400 MHz,Deuterium Oxide) δ 7.20 (dd, J=8.2, 1.2 Hz, 1H), 6.84 (d, J=2.1 Hz, 1H),6.77 (dd, J=8.3, 2.2 Hz, 1H), 3.19 (d, J=14.2 Hz, 1H), 2.99 (d, J=14.2Hz, 1H), 1.52 (s, 3H); MS (ESI) m/z 307 [M+H]+. Carbidopa4′-monophosphate: 1H NMR (400 MHz, Deuterium Oxide) δ 7.14 (t, J=1.4 Hz,1H), 7.01-6.83 (m, 2H), 3.19 (d, J=14.3 Hz, 1H), 3.00 (d, J=14.4 Hz,1H), 1.52 (s, 3H); MS (ESI) m/z 307 [M+H]+.

Example 4a Synthesis of Carbidopa Diphosphate

Carbidopa 3′,4′-diphosphate was prepared as shown in Scheme 4a below:

Specifically, carbidopa 3′,4′-diphosphate was prepared as described inSteps 1 through 4 below.

Step 1

A slurry of carbidopa monohydrate (20.0 g, 82 mmol), sodium bicarbonate(7.57 g, 90 mmol), water (200 mL), and THF (100 mL) was cooled to 5° C.to 10° C. and N-(benzyloxycarbonyloxy)succinimide (20.4 g, 82 mmol) wasadded. The mixture was warmed to ambient temperature and became a nearlyhomogeneous solution over 5 hours, when LC-MS showed nearly completereaction. The solution was diluted with MTBE (100 mL), the layersseparated, and organic layer extracted with saturated aqueous NaHCO₃(100 mL). The aqueous layers were acidified with 2 N HCl (160 mL) andthe acidic aqueous layer was extracted with MTBE (2×100 mL). During thesecond back-extraction, a small amount of product began to precipitate.The combined organic layers were washed with brine (20 mL) and residualsolid rinsed out of the separatory funnel with MTBE (20 mL). Theresulting mixture was concentrated to 43 g total mass and 10% THF/MTBE(60 mL) was added. The mixture was too thick to stir, so additional MTBE(60 mL to 6 vol 5% THF/MTBE) was added. The resulting white slurry wasthen heated to 50° C. The slurry was cooled to ambient temperature overone hour and then stirred for 14 hours. The white solid was filtered,washed with 5% THF/MTBE (20 mL), and dried in a vacuum oven (50° C.),giving(S)-2-(2-((benzyloxy)carbonyl)-hydrazinyl)-3-(3,4-dihydroxyphenyl)-2-methylpropanoicacid compound with THF (4:3) (31.1 g, 71.9 mmol, 91% yield) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (d, J=9.0 Hz, 2H), 8.18 (br s,1H), 7.49-7.17 (m, 5H), 6.59 (dd, J=5.0, 3.0 Hz, 2H), 6.44 (dd, J=8.0,2.0 Hz, 1H), 5.04 (s, 2H), 2.73 (d, J=13.4 Hz, 1H), 2.59 (d, J=13.3 Hz,1H), 1.07 (s, 3H); MS (ESI) m/z 361 [M+H]+.

Step 2

A solution of benzophenone hydrazone (20.0 g, 102 mmol) in DCM (100 mL)was cooled to <0° C. and iodine (0.052 g, 0.204 mmol) and1,1,3,3-tetramethylguanidine (25.6 mL, 204 mmol) were added. m-CPBA(30.5 g, 132 mmol) was added portion-wise between −10° C. and 0° C. over5 minutes (exothermic, dry ice/acetone bath to control). The mixture wasstirred between 0° C. and 12° C. for 15 minutes and then washed withwater (3×200 mL). The resulting mixture was dried (Na₂SO₄), concentratedto 76 mL total volume, and rinsed into a 125 mL Erlenmeyer flask with anadditional 16 mL of DCM, to make an approximately 1 M dark purplesolution of (diazomethylene)dibenzene. In a separate flask, a slurry of(S)-2-(2-((benzyloxy)carbonyl)hydrazinyl)-3-(3,4-dihydroxyphenyl)-2-methylpropanoicacid compound with tetrahydrofuran (4:3) (30.7 g, 74.0 mmol) in IPA (300mL) was cooled to less than 10° C. and the (diazomethylene)dibenzenesolution (78 mL, 78 mmol) was added. The resulting mixture was warmed toroom temperature and LC-MS showed a stalled reaction after 30 minutes.Additional diphenyldiazomethane (0.2 eq, 14 mL) was added and stirringcontinued at room temperature. After 35 minutes, the remainingdiphenyldiazomethane solution (9 mL) was added. After 2 hours, 20minutes, a purple color persisted and LC-MS showed that the reaction wascomplete. The reaction mixture was concentrated to approximately 60 mLand 20% aq. CH₃CN (300 mL) was added. The mixture was washed withcyclohexane (10×300 mL), ethyl acetate (450 mL) added, and the mixturewas washed with saturated aqueous NaHCO₃ (150 mL) and brine (60 mL). Themixture was dried (Na₂SO₄) and concentrated, giving (S)-benzyl2-(1-(benzhydryloxy)-3-(3,4-dihydroxyphenyl)-2-methyl-1-oxopropan-2-yl)hydrazine-carboxylate(39.4 g, 74.8 mmol, >99% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (br s,2H), 8.19 (br s, 1H), 7.43-7.20 (m, 15H), 6.70 (s, 1H), 6.55 (d, J=2.0Hz, 1H), 6.45 (d, J=8.0 Hz, 1H), 6.20 (dd, J=7.9, 2.0 Hz, 1H), 4.95 (d,J=3.4 Hz, 2H), 2.81 (d, J=13.6 Hz, 1H), 2.67 (d, J=13.7 Hz, 1H), 1.17(d, J=3.1 Hz, 3H); MS (ESI) m/z 549 [M+Na]+.

Step 3

A solution of (S)-benzyl2-(1-(benzhydryloxy)-3-(3,4-dihydroxyphenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate(39.4 g, 74.8 mmol) and CH₃CN (394 mL) was cooled to less than 0° C. andDBU (27.1 mL, 180 mmol) and tetrabenzyl pyrophosphate (89 g, 165 mmol)were added at less than 0° C. After 40 minutes, water (400 mL) was addedgiving a biphasic solution. The layers were separated, the bottom(yellow oil) layer was washed (approximately 100 mL) with cold 1:1CH₃CN/water (2×100 mL), then diluted with ethyl acetate (400 mL), andwashed with brine (80 mL). the mixture was dried (Na₂SO₄) andconcentrated. FCC (50-100% MTBE/heptanes) gave (S)-benzyl2-(1-(benzhydryloxy)-3-(3,4-bis((bis(benzyloxy)phosphoryl)oxy)phenyl)-2-methyl-1-oxopropan-2-yl)hydrazine-carboxylate(67.2 g, 64.2 mmol, 86% yield) as a clear oil. ¹H NMR (400 MHz, DMSO-d₆)δ 7.45-7.16 (m, 35H), 7.06 (d, J=8.6 Hz, 1H), 6.88 (dd, J=8.7, 2.0 Hz,1H), 6.71 (s, 1H), 5.12 (ddt, J=9.9, 7.0, 3.9 Hz, 10H), 4.99-4.80 (m,2H), 2.95-2.76 (m, 2H), 1.11 (d, J=1.8 Hz, 3H); MS (ESI) m/z 1069[M+Na]+.

Step 4

A solution of (S)-benzyl2-(1-(benzhydryloxy)-3-(3,4-bis((bis(benzyloxy)-phosphoryl)oxy)phenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate(60.6 g, 57.9 mmol) in THF (550 mL) was added to 5% Pd/C (wet JM#9)(12.1 g, 56.9 mmol) in a 2 L stainless steel pressure bottle. Themixture was shaken under 60 psi of hydrogen at 22° C. for 2 hours. Thestarting temperature was 12.4° C. (the solution had been stored in thefreezer) and the T_(max) was 31.6° C. Water (deionized, 275 mL) was thenadded and the hydrogenation was continued for another 17 hours. Themixture was filtered through a nylon membrane with 100 mL of washingwith 1:1 THF-water. The mixture was diluted with MTBE (100 mL) and thelayers were separated. The aqueous layer was washed with MTBE (3×100mL), then concentrated on a rotary evaporator (35° C. bath temperature)to 100 g total mass, and lyophilized for 3 days to a white glass. Theamorphous solid was broken up and lyophilized for one day to removetraces of additional water, giving carbidopa diphosphate (22.3 g, >99%)still containing 10 to 15 weight % water by Karl Fischer titration (85%corrected yield). ¹H NMR (500 MHz, DMSO-d₆) δ 7.15 (d, J=8.3 Hz, 1H),7.11 (s, 1H), 6.89 (dd, J=8.1, 2.1 Hz, 1H), 3.00-2.82 (m, 2H), 1.31 (s,3H); MS (ESI) m/z 387 [M+H]+. By HPLC (Agilent Poroshell 120 EC-C18#693975-902 4.6×150 mm column, 1 mL/minute 0.1% aq H₃PO₄/CH₃CN, 3 minute97.5:2.5, 4 minute gradient to 70:30, 2 minute gradient to 0:100, hold 1minute, detection at 220 nm), the material is 96.4% purity (peak area %at 220 nm; diphosphate retention time=2.37 minutes).

Example 4b Synthesis of Carbidopa Diphosphate

Carbidopa 3′,4′-diphosphate was prepared as shown in Scheme 4b below:

Specifically, carbidopa 3′,4′-diphosphate was prepared as described inSteps 1 through 4 below.

Step 1

To a suspension of S(−)-Carbidopa (25 g, 92 mmol) in water (76 mL) wasadded a solution of sodium hydroxide (7.24 g, 183 mol) in water (76 mL)drop-wise over a period of 20 minutes at <5° C. After the addition ofbase, the mixture was stirred for 15 minutes or until the reactionmixture was a solution. To this solution was added benzylchloroformate(18.67 g, 110 mmol) in THF (101 mL) drop-wise over a period of 30minutes at <10° C. and then the reaction mixture was allowed to warm tort. The reaction mixture was stirred at 25° C. for 1 hr. After 1 hr, anadditional 0.2 eq of benzylchloroformate (3.74 g, 3.12 mL) was added andthe reaction mixture was stirred 1.5 hr at 25° C. After 1.5 h, thereaction mixture (pH=5.75) was basified to pH=9 using 10% sodiumhydroxide and extracted with MTBE (3×150 mL). The organic layer wasseparated and discarded. The aqueous layer (pH=8.6) was acidified topH=2.75 using 6 N HCl and extracted with MTBE (3×150 mL). The combinedorganic layers was washed with saturated sodium chloride solution (150mL), dried over magnesium sulfate and partially (75%) concentrated undervacuum. To the solution was added 250 mL of THF and partially (75%)concentrated under vacuum again. To the yellow solution was added 250 mLof MTBE and concentrated to 50% by volume. The resulting white slurrywas cooled to 0° C., filtered and the solid washed with cold MTBE toafford 32.31 g (white solid) of Compound 1 (potency 84.5% w/w, 95.6% pa,PAY 83%).

Step 2

Cesium carbonate (2.3 g, 7.08 mmol) was added to a solution of Compound2 (5.0 g, 11.79 mmol) in DMF (50 mL) at 2° C. The mixture was stirredfor 10 mins. To this mixture was added benzyl bromide (2.0 g, 11.79mmol, 1.4 mL) dropwise over a period of 10 minutes at 2° C. After theaddition, the reaction mixture was stirred at 25° C. for 64 hr. After 64hr, the reaction mixture was diluted with water (150 mL) and extractedwith MTBE (3×150 mL). The combined organic layers was washed with water(50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated toafford 5.36 g of Compounds 2 and 3 in an 88% yield. Compound 2: MS (ESI)m/z 451 [M+H]+, Compound 3, MS (ESI) m/z 541 [M+H]+.

Step 3

To a solution of Compounds 2 and 3 (9.8 g, 21.75 mmol) in ACN (100 ml)was added tetrabenzyl pyrophosphate (29.9 g, 54.4 mmol) at −14° C. DBU(8.61 ml, 56.6 mmol) was added to the reaction mixture at −7° C.dropwise. The reaction mixture was then stirred at <0° C. for 30 mins.After 30 mins, the reaction mixture was allowed to warm to roomtemperature. After 1 h, the reaction mixture was quenched with water(300 mL), extracted with MTBE (2×150 mL), washed water (150 mL), brine(150 mL), dried (MgSO4), filtered and concentrated to afford 24.69 g ofCompounds 4 and 5 in a 92% yield. Compound 4, MS (ESI) m/z 972 [M+H]+.

Step 4

Tetrahydrofuran (10.00 mL) was added to Compounds 4 and 5 (1.026 g,0.980 mmol) and 5% Pd/C (50% wet JM#9) (0.199 g, 1.870 mmol, 0.10 g dryweight) in a 20 mL Barnstead w/glass liner. The mixture was stirredunder 80 psig of Hydrogen at 25° C. for 1.5 hr. Water (5.00 mL) wasadded and the mixture was hydrogenated for another 1.5 hr. Then after1.5 hr, the mixture was filtered through a polypropylene membrane, 2.5mL of MTBE was added, the mixture was shaken in a separatory funnel, andthe lower aqueous layer was drained. The aqueous solution was washedtwice with 2.5 mL of MTBE, giving a significant reduction in volume (THFand toluene pulled into the MTBE). The colorless aq. solution (waterlayer) was lyophilized for 3 days, giving 385 mg of the desired product(93.9% pa) compound 6.

Example 5 Alternative Synthesis of L-Dopa 4′-Monophosphate

L-Dopa 4′-monophosphate was prepared as shown in Scheme 5 below:

Specifically, L-Dopa 4′-monophosphate was prepared as described in Steps1 through 5 below.

Step 1

To a solution of 3-(benzyloxy)-4-hydroxybenzaldehyde, Compound 1, (10.0g, 43.8 mmol) in acetonitrile (100 ml) tetrabenzyl diphosphate (TBPP)(24.8 g, 46.0 mmol) at 25° C. was added. The reaction mixture was cooledto 4° C. and DBU (7.67 g, 50.4 mmol) was added to the reaction mixture.After the addition, the reaction mixture was allowed to warm to roomtemperature and stirred at room temperature (˜20-25° C.) for 60 mins.The reaction mixture was then quenched with water (400 ml) and extractedwith MTBE (3×100 mL). The organic layer was washed with saturated sodiumbicarbonate solution (150 mL), water (150 mL), saturated sodium chloridesolution (150 mL), and concentrated to afford Compound 2 (20.7 g, 96.5%purity, 93% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 9.92 (s, 1H), 7.67 (dd,J=1.8, 0.9 Hz, 1H), 7.54 (dd, J=8.1, 1.8 Hz, 1H), 7.48-7.39 (m, 3H),7.35-7.22 (m, 13H), 5.22 (s, 2H), 5.09 (dd, J=8.2, 2.1 Hz, 4H).

Step 2

To a solution of (+/−)-benzyloxycarbonyl-alpha-phosphonoglycinetrimethylester (31.1 g, 94 mmol) and dibenzyl(2-(benzyloxy)-4-formylphenyl) phosphate, Compound 2, (44.3 g, 94%purity, 85 mmol) in 443 mL of DCM at 2° C. was added1,1,3,3-tetramethylguanidine (TMG) (11.78 g, 102 mmol). The resultingmixture was stirred at room temperature overnight. The next day thereaction mixture was washed with 3×222 mL of water and concentrated toafford 68.9 g of Compound 3. Compound 3 was then slurried with 40.5 g ofsilica gel 60 in 689 mL of ethyl acetate for 1 h and filtered. Thefiltrate was concentrated to afford 73.4 g of Compound 3 as an oil.Compound 3 was then precipitated at 4° C., and slurried in 350 mL ofMTBE at 4° C. for 1 hr. The slurry was then filtered and the solidwashed with cold MTBE. The solid was dried in the vacuum oven at 40° C.overnight to afford 50.4 g of Compound 3 (99.6% purity, 85% yield). ¹HNMR (400 MHz, DMSO-d₆) δ 7.60 (t, J=1.4 Hz, 1H), 7.44-7.18 (m, 23H),5.10 (qd, J=5.9, 2.6 Hz, 8H), 3.72 (s, 3H).

Step 3

Into a 2.0 gal reactor was charged Compound 3, methyl3-(3-(benzyloxy)-4-((bis(benzyloxy)phosphoryl)oxy)phenyl)-2-(((benzyloxy)carbonyl)amino)acrylate(446.31 g, 521 mmol) in 3.6 L of THF. This solution was sparged with N₂for 30 minutes. Into another 2.0 gal reactor was charged1,2-bis[(2S,5S)-2,5-diethylphospholano]benzene(1,5-cyclooctadiene)rhodium(I)tetrafluoroborate (3.44 g, 5.21 mmol) and purged with N₂ 10 times thensparged with N₂ for 30 minutes. The starting material solution was thentransferred into this reactor using N₂ pressure. The lines were purgedwith H₂, then the reactor was purged with H₂ three times. The reactionwas stirred at 35° C. under 100 psig of H₂. After 20 hrs, HPLC showedCompound 4, with a 99% ee. The reaction solution was then transferredinto a 12 L extractor and 3.6 L of ethyl acetate was added. The solutionwas washed 2× with 3.7 L of 5 wt % cysteine/8% sodium bicarbonatefollowed by 3.6 L of 5 wt % aq NaCl. The organic layer was separated andstirred with 43.4 g of ENO-PC activated carbon at room temperature underN₂ overnight. The mixture was filtered and the filtrate concentrated toafford Compound 4 (420.1 g, (oil), 88% w/w purity, 100% yield, chiralpurity: 99% ee. The crude product (S)-methyl3-(3-(benzyloxy)-4-((bis(benzyloxy)phosphoryl)oxy)phenyl)-2-(((benzyloxy)carbonyl)amino)propanoate,Compound 4, was used, as is, in the next step. ¹H NMR (400 MHz, DMSO-d₆)δ 7.85 (d, J=8.1 Hz, 1H), 7.46-7.16 (m, 21H), 7.09 (dd, J=8.2, 1.4 Hz,1H), 6.81 (dd, J=8.2, 1.9 Hz, 1H), 5.09-4.98 (m, 8H), 4.31 (ddd, J=10.2,8.1, 5.0 Hz, 1H), 3.63 (s, 3H), 3.08-2.78 (m, 2H).

Step 4

To a 150-mL Parr hydrogenator was added 10 wt % on a dry basis of 5%Pd/C (1.33 g, catalyst contains 63.6% H2O). Charged a 2.9 wt % aqueoussodium bicarbonate solution (20.7 g) to the reactor. Compound 4 (5.70 g,85% potency) was dissolved in THF (48.5 mL, 10 mL/g of substrate) andthen transferred to the reactor. Pressurized the reactor with argon to60 psig and vented pressure to 10 psig; perform argon pressure purge atotal of 6 times. In a similar fashion, pressure purged the reactor withhydrogen 3 times (fill to 50 psig, vent to 5 psig). Refilled the reactorto 50 psig of H2 and agitated at 750 rpm at 25° C. for at least 2 h.Following reaction completion, filtered the biphasic solution to removethe catalyst. Rinsed the reactor and filter cake with water (4.1 mL, 2mL/g relative to theoretical yield of product). The biphasic reactionmixture was diluted with 16 mL of MTBE. The aqueous layer was removedand washed with 16 mL of MTBE. The aq layer was then transferred to a250-mL flask and quantity sufficient 6 M aq HCl was added to adjust topH 1.8. Mixed the solution vigorously, then added iPrOH (73 mL) to bringfinal solvent composition to 3:1 iPrOH/water. The slurry was stirredovernight. The crystallization slurry was filtered and the wetcakesolids were washed with iPrOH. The white solid was dried in the vacuumoven at 50° C. to afford Compound 5 (1.72 g, crystalline solid, 85%yield). 1H NMR (400 MHz, Deuterium Oxide) δ 7.25 (dt, J=8.3, 1.1 Hz,1H), 6.87 (t, J=1.5 Hz, 1H), 6.80 (dd, J=8.3, 2.2 Hz, 1H), 4.41 (ddd,J=7.9, 5.4, 0.7 Hz, 1H), 3.87 (d, J=0.7 Hz, 3H), 3.36-3.08 (m, 2H).

Step 5

To a solution of Compound 5, (S)-methyl2-amino-3-(3-hydroxy-4-(phosphonooxy)phenyl)propanoate, (10.0 g, 34.3mmol) in 40 mL of water at 15-20° C. was added 22.89 mL (4.0 eq) of 6 NNaOH. When the pH reached 7-8 the solution was passed through a filterfor clarification. After clarification, the pH adjustment was continued.After the base was added, the rxn was stirred at 25° C. for 60 mins(pH=12.06). After 60 mins the reaction mixture was acidified with 4.0 eq6N HCL (137 mmol, 22.89 mL). The final pH was adjusted to 1.8. After 10mins the rxn mixture became cloudy and 200 mL of IPA was added. Theslurry was stirred for 30 mins and the solid was filtered and washedwith IPA. The solid was dried in the vacuum oven at 40° C. overnight toafford Compound 6,(S)-2-amino-3-(3-hydroxy-4-(phosphonooxy)phenyl)propanoic acid (7.85 g,99% purity, 87% yield, 99.6% ee). ¹H NMR (400 MHz, Deuterium Oxide) δ7.24 (dd, J=8.3, 1.3 Hz, 1H), 6.91 (d, J=2.1 Hz, 1H), 6.83 (dd, J=8.3,2.2 Hz, 1H), 4.25 (dd, J=8.0, 5.2 Hz, 1H), 3.35-3.05 (m, 2H).

Example 6 Alternative Synthesis of L-Dopa 4′-Monophosphate

L-Dopa 4′-monophosphate was prepared as shown below:

Step 1

A solution of 2-(benzyloxy)phenol (63.7 ml, 364 mmol) in MeOH (1050 ml)was cooled to −10° C. and sodium iodide (54.5 g, 364 mmol) and sodiumhydroxide (382 ml, 764 mmol) were added (NaOH over 5 min, temp to 10° C.and dark solution with NaOH addition). Cooled back to <5° C. and addedsodium hypochlorite (247 ml, 400 mmol) dropwise, keeping the temperatureat <5° C. After 10 min, removed 500 mL MeOH by rotary evaporation, thenadded MTBE (730 mL) and 2 N HCl (909 ml, 1818 mmol), washed with 1 NNa₂S₂O₃ (130 mL×3; lighter each time) and brine (64 mL), dried (Na₂SO₄),conc, and flushed with cyclohexane (100 mL) to a crude yellow solid.Added cyclohexane (130 mL), heated to 55° C. (yellow solution), thencooled slowly, seeding at 45° C. (˜50 mg-solution) and 40° C. (˜50 mg,slurry developed). Continued cooling to room temperature (˜20-25° C.)and stirred vigorously overnight. Filtered, washing with cyclohexane (64mL), giving crop 1 material (69.93 g, 59%, very pure by 1H NMR, slightlyoff-white solid). Concentrated the mother liquors to ˜70 mL, seeded,aged 1 h, and sticky dark material was precipitating with product. AddedMTBE (7 mL), sonicated (good for color dissolution), stirred 20 min, andfiltered. Washed with 10% MTBE/cyclohexane (32 mL), giving crop 2material (4.65 g, some small impurities by 1H NMR). Overall, isolated2-(benzyloxy)-4-iodophenol (74.6 g, 229 mmol, 62.9% yield). ¹H NMR (501MHz, DMSO-d6) δ 9.33 (s, 1H), 7.49-7.42 (m, 2H), 7.42-7.35 (m, 2H),7.35-7.29 (m, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.09 (dd, J=8.3, 2.1 Hz, 1H),6.64 (d, J=8.3 Hz, 1H), 5.09 (s, 2H).

Step 2

A solution of (S)-benzyl2-(((benzyloxy)carbonyl)amino)-3-hydroxypropanoate (150 g, 455 mmol) inDMF (750 ml) was cooled to 0° C. and methyltriphenoxyphosphonium iodide(247 g, 547 mmol) was added (no exotherm). After 20 min between 5 and−5° C., complete by LC-MS. After 30 min, added sodium bicarbonate (19.13g, 228 mmol) and MTBE (750 mL, temp to 8° C.), then carefully addedwater (750 mL, minor CO₂ evolution early in addition), keeping the temp<20° C. Washed into a separatory funnel with additional water (750 mL,total 1.5 L, 10 vol) and MTBE (750 mL, total 1.5 L, 10 vol), aq pH˜8.Separated layers, washed the organic layer with brine (300 mL), andchecked layers by LC-MS. Dried (Na₂SO₄), conc to minimal volume (401 gtotal mass), and added MeOH (3.0 L, yellow solution). Added water (1.5L) over 30 min, seeding with previously isolated crystalline material(0.1 wt %, 150 mg) after 2 vol, 300 mL water had been added (did notdissolve). A slurry gradually developed, then rapidly thickened after650 mL water had been added. After stirring at ambient temperature for30 min, filtered the white slurry, washing with 2:1 MeOH/water (300 mLslurry wash, 300 mL displacement wash) and left on the glass frit withvacuum for 12 h. Added MeOH (2.25 L, 15 vol) to the wet cake, stirredvigorously for 30 min to break up the slurry, then added water (1.125 L)over 30 min, stirred additional 15 min, and filtered, washing with 2:1MeOH/water (300 mL displacement wash). Dried the white solid in a vacuumoven at 50° C. to constant weight, giving (R)-benzyl2-(((benzyloxy)carbonyl)amino)-3-iodopropanoate (173 g, 394 mmol, 86%yield). K_(f) titration showed 253 ppm water. ¹H NMR (400 MHz, DMSO-d6)δ 7.96 (d, J=8.3 Hz, 1H), 7.44-7.14 (m, 10H), 5.10 (d, J=33.8 Hz, 4H),4.38 (td, J=8.7, 4.6 Hz, 1H), 3.55 (dd, J=10.3, 4.6 Hz, 1H), 3.37 (t,J=9.7 Hz, 1H). MS (ESI) m/z 457 [M+NH₄]⁺.

Step 3

A slurry of zinc (47.0 g, 719 mmol) and DMF (325 ml) was stirred in a 2L 3-neck round-bottom flask with magnetic stirring. The gray slurry wascooled to 16° C. in an ice bath and iodine (7.60 g, 29.9 mmol) was added(yellow to clear supernatant immediately with exotherm from 16 to 27°C.). Cooled back to 10° C. and added (R)-benzyl2-(((benzyloxy)carbonyl)amino)-3-iodopropanoate (105 g, 240 mmol)portionwise over 10 min at <25° C. After an additional 10 min between 20and 25° C., LCMS showed complete zinc insertion (aliquot 2N HCl quench).Added Pd₂(dba)₃ (0.457 g, 0.499 mmol),2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.410 g, 0.998 mmol),and 2-(benzyloxy)-4-iodophenol (65.1 g, 200 mmol) in one portion (noexotherm) and stirred at room temperature (start=2:30). After 1 h, anexotherm to 27° C. was observed, so cooled in a room temperature waterbath back to 20-25° C. and stirred overnight. After 15 h, 40 min, LC-MSshowed complete and clean reaction. Added MTBE (650 mL) and silica (65g), stirred 15 min, and filtered the gray slurry, washing the gray solidwith MTBE (325+130 mL). Washed the yellow filtrate with satd aq NH₄Cl(325 mL, temp to 27° C. with a small amount of H₂ evolution, at pH ˜5-6)and brine (130 mL), dried (Na₂SO₄), conc, and FCC (800 g column, 50-100%DCM/heptanes, then to 10% MTBE/DCM; only separating non-polar highlycolored impurities and baseline material, upgrading HPLC pa % from 91 to93 pa %) gave (S)-benzyl3-(3-(benzyloxy)-4-hydroxyphenyl)-2-(((benzyloxy)carbonyl)amino)propanoate(106 g, 207 mmol, 104% yield) as a light brown oil. ¹H NMR showed extramass primarily CBz alanine Bn ester from protonation of excess alkylzincduring workup. Used without further purification in the next step,assuming quantitative yield. ¹H NMR (501 MHz, DMSO-d6) δ 8.86 (s, 1H),7.80 (d, J=8.0 Hz, 1H), 7.47-7.41 (m, 2H), 7.41-7.08 (m, 13H), 6.94 (d,J=2.0 Hz, 1H), 6.70 (d, J=8.0 Hz, 1H), 6.63 (dd, J=8.0, 1.9 Hz, 1H),5.15-4.93 (m, 6H), 4.27 (ddd, J=9.7, 7.9, 5.5 Hz, 1H), 2.93 (dd, J=13.8,5.5 Hz, 1H), 2.78 (dd, J=13.8, 9.8 Hz, 1H). MS (ESI) m/z 512 [M+H]⁺.

Step 4

A solution of (S)-benzyl3-(3-(benzyloxy)-4-hydroxyphenyl)-2-(((benzyloxy)carbonyl)amino)propanoate(102 g, 200 mmol) in ACN (510 ml) was stirred at room temperature andtetrabenzyl pyrophosphate (118 g, 220 mmol) was added. Cooled in an icebath and added DBU (45.2 ml, 300 mmol) over 10 min, keeping the tempbetween 20 and 25° C. After 30 min, LC-MS showed complete reaction.Added MTBE (1.0 L) and water (510 mL), separated layers (very little aqloss by LCMS), and washed the org layer with brine (3×200 mL). Dried(Na₂SO₄), conc, and FCC (split in two portions; each purified on an 800g column with 25-75% MTBE/heptanes gradient elution, then combined) gave(S)-benzyl3-(3-(benzyloxy)-4-((bis(benzyloxy)phosphoryl)oxy)phenyl)-2-(((benzyloxy)carbonyl)amino)propanoate(132 g, 171 mmol, 86% yield) as an amber oil. ¹H NMR (400 MHz, DMSO-d6)δ 7.87 (d, J=8.1 Hz, 1H), 7.43-7.17 (m, 26H), 7.07 (dd, J=8.2, 1.3 Hz,1H), 6.79 (dd, J=8.3, 1.9 Hz, 1H), 5.14-4.91 (m, 10H), 4.38 (ddd,J=10.0, 8.0, 5.2 Hz, 1H), 3.05 (dd, J=13.8, 5.2 Hz, 1H), 2.88 (dd,J=13.8, 10.1 Hz, 1H). MS (ESI) m/z 789 [M+NH₄]⁺.

The preparation of levodopa 4′-monophosphate was completed as with Step5a from Example 1.

Example 7 Alternative Synthesis of Carbidopa 4′-Monophosphate

Carbidopa 4′-monophosphate was prepared as shown in Scheme 7 below:

Specifically, Carbidopa 4′-monophosphate was prepared as described inSteps 1 through 5 below.

Step 1

A 500 mL three-neck round bottom flask was charged with compound 1(25.04 g, 90 mmol), tris(dibenzylideneacetone)palladium (1.23 g, 1.343mmol), tri-tert-butylphosphonium tetrafluoroborate (0.875 g, 3.02 mmol),and a stir bar. A thermocouple, reflux condenser, and stopper wereplaced onto the three necks of the flask. The flask was purged withnitrogen for 1 h. During this time, a second flask was charged withdioxane (200.0 mL), 2-methylprop-2-en-1-ol (8.30 mL, 99 mmol), andN-cyclohexyl-N-methylcyclohexanamine (30.0 mL, 140 mmol), and this flaskwas sparged with nitrogen for 1 h. The dioxane solution was thentransferred via cannula into the flask containing compound 1, palladiumand ligand. The reaction mixture was heated to 100° C. for 1 h. Afterthis time, the reaction was cooled to 35° C. and diluted with ethylacetate (250 mL) and 1.0 M HCl (250 mL). The biphasic mixture wasstirred for 10 min and phase cut. The organic solution was removed fromthe reactor and the aqueous phase returned. Ethyl acetate (150 mL) wasadded to the aqueous material and the mixture was agitated for 10 min.The aqueous layer was drained from the reaction, and the original ethylacetate was returned to the reactor. This combined mixture was washed(2×10 min with stirring) with 5% N-acetylcysteine/8% sodium bicarbonatemixture. After separating the aqueous waste after each wash, the yelloworganic solution was filtered through Celite® diatomaceous earth. KarlFischer titration of the organic reaction mixture showed that thecontent of water was 3.3 wt %. The yellow organic solution was returnedto the reactor and stirred as sodium bisulfite (18.67 g, 179 mmol) wasadded. The reaction mixture was heated to 40° C. for 13 h. After thistime, the precipitate was filtered and the solid was washed with ethylacetate (3×100 mL) to give a white solid in 64.2% yield. The potency ofthe material was determined to be 60.0% by Q-NMR spectroscopy. 1H NMR(400 MHz, D2O, 1:1 diastereomers): δ ppm 7.48-7.36 (m, 5H), 6.92 (m,1H), 6.86 (dd, J=8.0, 4.0 Hz, 1H), 6.76 (dd, J=8.0, 4.0 Hz, 1H),5.21-5.19 (m, 2H), 4.27-4.25 (m, 1H), 3.10-3.05 (m, 0.5H), 2.68-2.63 (m,0.5 H), 2.52-2.49 (m, 0.5H), 2.38-2.16 (m, 1.5H), 0.94 (d, J=8.0 Hz,1.5H), 0.84 (d, J=8.0 Hz, 1.5 H).

Step 2a

To a 500-mL 3-neck round bottom flask with attached thermocouple andoverhead stirring was charged compound 3 (15.05 g, 63.3% w/w, 23.2 mol),sodium bicarbonate (16.97 g, 202 mmol), water (155 mL) and ethyl acetate(140 mL). The resulting biphasic suspension was stirred vigorously at25° C. After the complete consumption of starting material, the reactionwas transferred to a separatory funnel and the layers separated. Theorganic layer was washed with brine (75 mL). The organic layer was driedover sodium sulfate, and concentrated in vacuo to provide compound 2 asa white solid (6.22 g, 62.9%). 1H NMR (400 MHz, CDCl₃): δ ppm 9.68 (d,J=2.0 Hz, 1H), 7.46-7.32 (m, 5H), 6.86 (d, J=8.0 Hz, 1H), 6.73 (d, J=1.6Hz, 1H), 6.68 (dd, J=8.0, 1.6 Hz, 1H), 5.58 (s, 1H), 5.08 (s, 2H), 2.98(dd, J=13.6, 6.0 Hz, 1H), 2.65-2.56 (m, 1H), 2.53 (dd, J=13.6, 8.0 Hz,1H), 1.05 (d, J=6.8 Hz, 3H).

Step 2b

To a 250-mL 3-neck flask with attached thermocouple and overheadstirring was added compound 2 (6.29 g, 23.22 mmol) followed byacetonitrile (63 mL). Then tetrabenzyl pyrophosphate (13.54 g, 24.38mmol) was added at 25° C. The reaction was cooled to 2.1° C. in an icebath and DBU (4.55 mL, 30.2 mmol) was added to the reaction mixturedropwise and the resulting solution was stirred at 2° C. After thecomplete consumption of starting material, the reaction mass was dilutedwith water (65 mL) and extracted with MTBE (130 mL). The combinedorganic layer was washed with water (65 mL), 5% sodium chloride solution(30 mL), dried over sodium sulfate, and concentrated in vacuo to providecrude compound 4 as a yellow oil (11.38 g, 92.4%). 1H NMR (400 MHz,CDCl₃): δ ppm 9.75 (d, J=1.2 Hz, 1H), 7.46-7.42 (m, 2H), 7.36-7.23 (m,13H), 7.17 (dd, J=8.0, 1.2 Hz, 1H), 6.81 (dd, J=2.0, 1.2 Hz, 1H), 6.72(dd, J=8.0, 2.0 Hz, 1H), 5.11 (s, 2H), 5.10 (s, 2H), 5.07 (s, 2H), 3.05(dd, J=13.6, 5.6, Hz, 1H), 2.69-2.59 (m, 1H), 2.56 (dd, J=13.6, 8.0 Hz,1H), 1.09 (d, J=7.2 Hz, 3H).

Step 3

To a 500-mL 3-neck round bottom flask with attached thermocouple wasadded (R)-5-(pyrrolidin-2-yl)-1H-tetrazole (0.15 g, 1.07 mmol) andacetonitrile (40 mL). TFA (0.084 mL, 1.07 mmol) was then added followedby (E)-dibenzyl diazene-1,2-dicarboxylate (8.25 g, 27.7 mmol). Then asolution of compound 4 (11.4 g, 21.49 mmol) in acetonitrile (70 mL) wasadded via cannula. The resulting solution was stirred at 25° C. Afterthe complete consumption of starting material, the reaction mixture wasdiluted with acetonitrile (88 mL) and water (58 mL) was added toprecipitate the product. The resulting slurry was stirred overnight at25° C. and then filtered and washed with 28 wt % water in acetonitrile(30 mL) to provide compound 5 (8.9 g, 50% yield) as a white solid. 1HNMR (400 MHz, CDCl₃): δ ppm 9.72 (s, 1H), 7.42-7.17 (m, 25H), 7.09-7.05(m, 1H), 6.67-6.34 (m, 2H), 5.80 (bs, 1H), 5.30-4.80 (m, 10H), 3.39-3.21(m, 1H), 2.92-2.77 (m, 1H), 1.14-1.00 (bs, 3H).

Step 4

A 100 mL three-neck round bottom flask was fit with a thermocouple andcharged with compound 5 (5.10 g, 6.15 mmol), acetonitrile (50.0 mL), anddimethyl sulfoxide (DMSO) (1.00 mL, 14.1 mmol). The white suspension wasstirred and a 2.0 mL water solution of sodium dihydrogenphosphatemonohydrate (1.78 g, 12.90 mmol) was prepared and added to the reaction.Following this addition, a 2.0 mL water solution of sodium chlorite(2.88 g (80 wt %), 25.5 mmol) was added dropwise over 90 s. The cloudyreaction turned light yellow and more deep yellow and became more clearas the reaction proceeded. After 90 min, the reaction was quenched witha 6.0 mL water solution of sodium sulfite (1.60 g, 12.7 mmol). Thereaction was stirred for 20 min after the sulfite addition. After thistime, the reaction was poured into a separatory funnel and the roundbottom flask was rinsed with 50 mL of isopropyl acetate and 50 mL ofwater. The aqueous and organic layers were separated. The organic layerwas washed with 50 mL of water. An emulsion formed upon shaking thelayers. At this time, 20 mL of brine was then added and the phasesseparated upon disappearance of the emulsion. An additional 50 mL ofisopropyl acetate was added to the reaction, and the flask was put on arotary evaporator until the reaction mixture appeared cloudy. The totalvolume of the reaction mixture after distillation was ˜10 mL. Thereaction flask was put into the 4° C. refrigerator for 16 h. After thistime, the white solid that formed was collected, washed with 20 mL ofisopropyl acetate, and dried in vacuo to give 75.0% yield of compound 6.1H NMR (400 MHz, CDCl3): δ ppm 7.58-7.14 (m, 26H), 7.01-6.84 (m, 1H),6.41-6.29 (m, 1H), 5.46-4.64 (m, 10H), 3.80-3.49 (m, 1H), 3.02-2.94 (m,1H), 1.19 (br s, 3H).

Step 5

A 1-gallon Parr reactor was charged with 5 wt % dry basis of 5% Pd/C(63.6% H2O, 15.0 g), water (182 mL) and 5 wt % aqueous sodiumbicarbonate (215 mL). To the aqueous catalyst slurry was added a THFsolution (1090 mL) of compound 6 (109 g, 85% potent). The reactor wasassembled and inerted with nitrogen, followed by purging with hydrogen(4×30 psig pressure purges). The reactor was then re-pressurized to 30psig with hydrogen. The reactor was vigorously agitated at 25° C. for atleast 1 h. Upon obtaining complete reaction conversion, hydrogen wasvented and the reactor was inerted with nitrogen. The biphasic reactionmixture was then filtered to remove the catalyst, followed by rinsingwith water (93 mL). The biphasic reaction mixture was diluted with MTBE(370 mL). The mixture was stirred for 15 min, then allowed to settle for10 min (note the product is contained in the aqueous layer). Separatedthe layers and washed the aqueous layer with MTBE (370 mL) as describedabove.

Using quantity sufficient 6 M aqueous HCl, the solution is acidified topH 1.9. Seeded the aqueous solution with 0.1 wt % of compound 7 toinduce nucleation. Added isopropanol (1326 mL) to the seed slurry andmixed for at least 5 h at ambient temperature. The slurry was filteredto collect the product, recirculating the liquors as a rinse ifnecessary. Washed the wetcake solids with isopropanol (370 mL). Theproduct solids were air-dried on the funnel for 2 h. Isolated 38.5 g ofcompound 7 as the trihydrate (97.2% potency adjusted yield). 1H NMR (400MHz, D2O): δ ppm 7.21 (d, J=8.0 Hz), 6.87 (d, J=2.0 Hz, 1H), 6.77 (dd,J=8.0, 2.0 Hz, 1H), 3.19 (d, J=16.0 Hz, 1H), 3.00 (d, J=16.0 Hz, 1H),1.54 (s, 3H).

Example 8 Synthesis of L-Dopa 3′-Phonoxymethyl Ester

L-dopa 3′-phonoxymethyl ester was prepared as shown in Scheme 8 below:

Specifically, L-dopa 3′-phonoxymethyl ester was prepared as described inSteps 1 through 6 below.

Step 1

To a solution of 4-(benzyloxy)-4-hydroxybenzaldehyde, Compound 1, (10.0g, 43.8 mmol) in acetonitrile (133 ml) was addeddi-tert-butyl(chloromethyl)phosphate (12.53 g, 46.0 mmol) at 25° C. Thereaction mixture was cooled to 4° C. and DBU (7.67 g, 50.4 mmol) wasadded. After the addition, the reaction mixture was allowed to warm toroom temperature (˜20-25° C.) and then heated to 50° C. for 39 h. After22 h the reaction mixture cooled to room temperature and quenched withwater (400 ml) and extracted with MTBE (3×100 mL). The organic layer waswashed with saturated sodium bicarbonate solution (150 mL), water (150mL), saturated sodium chloride solution (150 mL), and concentrated toafford Compound 2 (19.48 g, 49% purity, 50% yield. The crude product waspassed down a silica gel column using a ethyl acetate-hexane gradient toafford 8.08 g of Compound 2 (94% purity, 40% yield. ¹H NMR (400 MHz,DMSO-d₆) δ 9.85 (s, 1H), 7.66 (dd, J=8.3, 1.9 Hz, 1H), 7.63 (d, J=2.0Hz, 1H), 7.49-7.44 (m, 2H), 7.43-7.32 (m, 4H), 5.65 (d, J=12.0 Hz, 2H),5.25 (s, 2H), 1.36 (d, J=0.6 Hz, 18H).

Step 2

To a solution of (+/−)-benzyloxycarbonyl-alpha-phosphonoglycinetrimethylester (5.35 g, 16.14 mmol) and2-(benzyloxy)-5-formylphenoxy)methyl di-tert-butyl phosphate, Compound2, (6.78 g, 14.67 mmol) in 70 mL of DCM at 0° C. was added1,1,3,3-tetramethylguanidine (TMG) (2.0 g, 17.60 mmol). The resultingreaction mixture was stirred at room temperature overnight. The next daythe reaction mixture was washed with 3×35 mL of water and concentratedto afford 13.11 g of crude product. The crude product was then purifiedby column chromatography on silica gel using ethyl acetate-hexanegradient to afford 7.34 g of Compound 3 (81% purity, 62% yield. ¹H NMR(400 MHz, DMSO-d₆) δ 7.50-7.28 (m, 13H), 7.21 (s, 1H), 7.16 (s, 1H),5.59 (d, J=11.9 Hz, 2H), 5.18 (s, 2H), 5.09 (d, J=12.1 Hz, 2H), 3.69 (s,3H), 1.35 (d, J=0.5 Hz, 18H).

Step 3

Into a 120 ml parr reactor was charged methyl3-(4-(benzyloxy)-3-(((di-tert-butoxyphosphoryl)oxy)methoxy)phenyl)-2-(((benzyloxy)carbonyl)amino)acrylate,Compound 3, (7.34 g, 9.07 mmol) and1,2-bis[(2S,5S)-2,5-diethylphospholano]benzene(1,5-cyclooctadiene)rhodium(I)tetrafluoroborate (0.060 g, 0.091 mmol) and tetrahydrofuran (59.5 ml).The mixture was purged with H₂ and the reaction mixture was stirred at35° C. under 100 psig of H₂ for 20 hrs. After 20 hrs, the reactionmixture was concentrated and purified by column chromatography on silicagel using ethyl acetate-hexane gradient to afford 5.44 g of Compound 4(76% purity, 69% yield, 98% ee). ¹H NMR (400 MHz, DMSO-d₆) δ 7.80 (d,J=8.0 Hz, 1H), 7.48-7.25 (m, 10H), 7.04 (d, J=2.1 Hz, 1H), 7.01 (d,J=8.4 Hz, 1H), 6.89 (dd, J=8.3, 2.1 Hz, 1H), 5.55 (dd, J=11.6, 1.6 Hz,2H), 5.08 (s, 2H), 4.99 (d, J=2.7 Hz, 2H), 4.22 (ddd, J=9.8, 7.9, 5.2Hz, 1H),), 3.62 (s, 3H), 3.03-2.67 (m, 2H), 1.37 (d, J=1.2 Hz, 18H).

Step 4

Into a 50 mL parr reactor was charged 5% Pd/C (JM #9) (0.418 g, 2.311mmol). The (S)-methyl3-(4-(benzyloxy)-3-(((di-tert-butoxyphosphoryl)oxy)methoxy)phenyl)-2-(((benzyloxy)carbonyl)amino)propanoate,Compound 4, (2.0 g, 2.311 mmol) was dissolved in tetrahydrofuran (15.2ml). This solution was charged into the reactor and purged with argonfollowed by H₂. The reaction mixture was stirred under 50 psig of H₂ atroom temperature for 1 hour. After 1 h, the catalyst was filtered offand washed with THF. The solution was concentrated and purified bycolumn chromatography on silica gel using ethyl acetate-methanol toafford 1.04 g of Compound 4, (95% purity, 98% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 9.13 (s, 1H), 6.88 (d, J=1.9 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H),6.71 (d, J=2.0 Hz, 1H), 5.50 (d, J=11.4 Hz, 2H), 3.58 (s, 3H), 3.49 (t,J=6.6 Hz, 1H), 2.81-2.58 (m, 2H), 1.70 (s, 2H), 1.39 (d, J=0.6 Hz, 18H).

Step 5

(S)-methyl2-amino-3-(3-(((di-tert-butoxyphosphoryl)oxy)methoxy)-4-hydroxyphenyl)propanoate,Compound 5, (1.04 g, 2.34 mmol) in 10 mL of DCM at 5° C. was added 876uL (5.0 eq) of trifluoroacetic acid dropwise. The reaction mixture wasstirred at 25° C. until completed. After 60 mins, the starting materialwas consumed and the product gummed out of the DCM layer. The product,Compound 6, was extracted from the DCM layer with 3 mL of water. Theaqueous layer was then taken, as is, to the next step. LC/MS [M+1]=322.1

Step 6

(S)-methyl2-amino-3-(4-hydroxy-3-((phosphonooxy)methoxy)phenyl)propanoate,Compound 6, (752 mg, 2.341 mmol) in 4 mL of water at 5° C. was added2.62 mL of 6 N NaOH dropwise over 5 min to a pH=12.5. The rxn mixturewas stirred at 25° C. until completed. After 60 mins the reactionmixture was acidified with 6N HCL to a pH=1.9. To this solution wasadded IPA until the product precipitated out while maintaining the pH of1.9. The product, Compound 7, was filtered and washed with IPA toafford, 630 mg, with a purity of 90%. ¹H NMR (400 MHz, Deuterium Oxide)δ 7.17 (d, J=1.8 Hz, 1H), 6.99-6.96 (m, 1H), 6.94 (dd, J=8.3, 1.8 Hz,1H), 5.57 (d, J=12.6 Hz, 2H), 4.16 (dd, J=7.9, 5.1 Hz, 1H), 3.33-3.05(m, 2H).

Example 9 Synthesis of L-Dopa 4′-Phonoxymethyl Ester

L-dopa 4′-phonoxymethyl ester was prepared as shown in Scheme 9 below:

Specifically, L-dopa 4′-phonoxymethyl ester was prepared as described inSteps 1 through 6 below.

Step 1

To a solution of 3-(benzyloxy)-4-hydroxybenzaldehyde, Compound 1, (10.0g, 43.8 mmol) in acetonitrile (133 ml) was addeddi-tert-butyl(chloromethyl)phosphate (12.53 g, 46.0 mmol) at 25° C. Thereaction mixture was cooled to 4° C. and DBU (7.67 g, 50.4 mmol) wasadded. After the addition, the reaction mixture was allowed to warm toroom temperature (˜20-25° C.) and then heated to 50° C. for 22 h. After22 h the reaction mixture cooled to room temperature and quenched withwater (400 ml) and extracted with MTBE (3×100 mL). The organic layer waswashed with saturated sodium bicarbonate solution (150 mL), water (150mL), saturated sodium chloride solution (150 mL), and concentrated toafford Compound 2 (20.0 g, 70% purity, 73% yield). The crude product waspassed down a silica gel column using a ethyl acetate-hexane gradient toafford 8.77 g of Compound 2 (91% purity, 41% yield. ¹H NMR (400 MHz,DMSO-d₆) δ 9.87 (s, 1H), 7.59 (d, J=7.0 Hz, 2H), 7.49-7.45 (m, 2H),7.43-7.31 (m, 4H), 5.72 (d, J=12.7 Hz, 2H), 5.20 (s, 2H), 1.37 (d, J=0.6Hz, 18H).

Step 2

To a solution of (+/−)-benzyloxycarbonyl-alpha-phosphonoglycinetrimethylester (5.51 g, 16.64 mmol) and(2-(benzyloxy)-4-formylphenoxy)methyl di-tert-butyl phosphate, Compound2, (7.49 g, 15.13 mmol) in 75 mL of DCM at 0° C. was added1,1,3,3-tetramethylguanidine (2.09 g, 18.16 mmol). The resultingreaction mixture was stirred at room temperature overnight. The next daythe reaction mixture was washed with 3×35 mL of water and concentratedto afford 13.11 g of crude product. The crude product was then purifiedby column chromatography on silica gel using ethyl acetate-hexanegradient to afford 8.37 g of Compound 3 (85% purity, 72% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 7.54 (d, J=2.0 Hz, 1H), 7.50-7.21 (m, 13H), 7.16(d, J=8.5 Hz, 1H), 5.63 (d, J=12.1 Hz, 2H), 5.09 (d, J=19.1 Hz, 4H),3.71 (s, 3H), 1.37 (d, J=0.5 Hz, 18H).

Step 3

Into a 120 ml parr reactor was charged methyl3-(3-(benzyloxy)-4-(((di-tert-butoxyphosphoryl)oxy)methoxy)phenyl)-2-(((benzyloxy)carbonyl)amino)acrylate(8.37 g, 10.85 mmol) and1,2-bis[(2S,5S)-2,5-diethylphospholano]benzene(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate (0.072 g, 0.109 mmol) and tetrahydrofuran(70.5 ml). The mixture was purged with H₂ and the reaction mixture wasstirred at 35° C. under 100 psig of H₂ for 20 hrs. After 20 hrs, thereaction mixture was concentrated and purified by column chromatographyon silica gel using ethyl acetate-hexane gradient to afford 6.34 g ofCompound 4 (78% purity, 69% yield, 97% ee). ¹H NMR (400 MHz, DMSO-d₆) δ7.80 (d, J=8.1 Hz, 1H), 7.54-7.22 (m, 10H), 7.12-6.97 (m, 2H), 6.80 (dd,J=8.2, 2.0 Hz, 1H), 5.54 (d, J=11.3 Hz, 2H), 5.13-4.90 (m, 4H), 4.25(ddd, J=10.1, 8.1, 5.0 Hz, 1H), 3.62 (s, 3H), 3.04-2.73 (m, 2H), 1.35(d, J=0.5 Hz, 18H).

Step 4

Into a 50 mL parr reactor was charged 5% Pd/C (JM #9) (0.429 g, 2.372mmol). The (S)-methyl3-(3-(benzyloxy)-4-(((di-tert-butoxyphosphoryl)oxy)methoxy)phenyl)-2-(((benzyloxy)carbonyl)amino)propanoate,Compound 4, (2.0 g, 2.372 mmol) was dissolved in tetrahydrofuran (THF)(15.6 ml). This solution was charged into the reactor and purged withargon followed by H₂. The reaction mixture was stirred under 50 psig ofH₂ at room temperature for 1 hour. After 1 h, the catalyst was filteredoff and washed with THF. The solution was concentrated and purified bycolumn chromatography on silica gel using ethyl acetate-methanol toafford 1.08 g of Compound 4, (94% purity, 99% yield). ¹H NMR (400 MHz,DMSO-d₆) δ 9.20 (s, 1H), 6.95 (d, J=8.2 Hz, 1H), 6.66 (d, J=2.1 Hz, 1H),6.54 (dd, J=8.2, 2.1 Hz, 1H), 5.49 (d, J=11.3 Hz, 2H), 3.57 (s, 3H),3.50 (t, J. 6.6 Hz, 1H), 2.79-2.59 (m, 2H), 1.72 (2, 2H), 1.38 (d, J=0.5Hz, 18H).

Step 5

(S)-methyl2-amino-3-(4-(((di-tert-butoxyphosphoryl)oxy)methoxy)-3-hydroxyphenyl)propanoate,Compound 5, (1.08 g, 2.34 mmol) in 11 mL of DCM at 5° C. was added 901uL (5.0 eq) of trifluoroacetic acid dropwise. The rxn mixture wasstirred at 25° C. until completed. After 60 mins, the starting materialwas consumed and the product gummed out of the DCM layer. The product,Compound 6, was extracted from the DCM layer with 3 mL of water. Theaqueous layer was then taken, as is, to the next step. LC/MS [M+1]=322.1

Step 6

(S)-methyl2-amino-3-(3-hydroxy-4-((phosphonooxy)methoxy)phenyl)propanoate,Compound 6, (752 mg, 2.341 mmol) in 3 mL of water at 5° C. was added 6 NNaOH dropwise over 5 min to a pH=12.5. The rxn mixture was stirred at25° C. until completed. After 60 mins the reaction mixture was acidifiedwith 6N HCL to a pH=1.9. To this solution was added IPA until theproduct precipitated out while maintaining the pH of 1.9. The product,Compound 7, was filtered and washed with IPA to afford, 850 mg, with apurity of 88%. ¹H NMR (400 MHz, Deuterium Oxide) δ 7.09 (dd, J=8.2, 0.7Hz, 1H), 6.76 (d, J=2.1 Hz, 1H), 6.73 (dt, J. 8.3, 1.3 Hz, 1H), 5.43(dd, J=12.6, 0.7 Hz, 2H), 4.08-3.97 (m, 1H), 3.21-2.89 (m, 2H).

Example 10 Synthesis of Carbidopa 3′-Phonoxymethyl Ester and Carbidopa4′-Phonoxymethyl Ester

Carbidopa 3′-phonoxymethyl ester and Carbidopa 4′-phonoxymethyl esterwere prepared as shown in Scheme 10 below:

Specifically, Carbidopa 3′-phonoxymethyl ester and Carbidopa4′-phonoxymethyl ester were prepared as described in Steps 1 through 3below.

Step 1—Preparation of (S)-benzyl2-benzyl-2-(1-(benzyloxy)-3-(3-(benzyloxy)-4-hydroxyphenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate(a mixture of 3′ and 4′) (Compound 2)

To a 500 mL round bottom flask were added(S)-2-(2-((benzyloxy)carbonyl)hydrazinyl)-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid compound with tetrahydrofuran(1:1), Compound 1, (10 g, 84 wt %, 19.42 mmol) and 100 mL DMF. Cesiumcarbonate (11.39 g, 35 mmol) was added, and the mixture was stirred atroom temperature for 15 minutes. The mixture was cooled in an ice bath.Benzyl bromide (7.38 mL, 62.2 mmol) was added portionwise. The mixturewas stirred in the ice bath overnight. The slurry was filtered, and thecake was washed with methyl t-butyl ether. The filtrate was mixed withwater, and the layers were separated. The aqueous layer was extractedwith methyl t-butyl ether. The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate, and concentrated. The crudewas purified by flash chromatography using a 220 g silica column (0-30%ethyl acetate in heptanes) to afford Compound 2 as a colorless thick oil(1.20 g, 9.8%).

MS (ESI+) 631.1

Step 2—Preparation of (S)-benzyl2-benzyl-2-(1-(benzyloxy)-3-(3-(benzyloxy)-4-(((bis(benzyloxy)phosphoryl)oxy)methoxy)phenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate(A Mixture of 3′ and 4′) (Compound 3)

To a 100 mL round bottom flask were added dibenzyl (chloromethyl)phosphate (1.632 g, 4.99 mmol), (S)-benzyl2-benzyl-2-(1-(benzyloxy)-3-(3-(benzyloxy)-4-hydroxyphenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate,Compound 2, (2.1 g, 3.33 mmol) and 25 mL acetonitrile. The mixture wascooled in an ice bath. 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.745 mL,4.99 mmol) was added, and the mixture was stirred in the ice bath for 30minutes, then at room temperature overnight. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetatetwice. The combined organic layers were washed with water and brine,dried over anhydrous sodium sulfate, and concentrated. The crude waspurified first by flash chromatography using a 120 g silica column(0-50% ethyl acetate in heptanes), followed by RP-HPLC (60-100%acetonitrile in 0.1% TFA/water on Phenonemex C18 5 u column) to affordCompound 3 as a colorless oil (247 mg, 8%).

LC/MS (APCI+) m/z=921.2(M+H)

Step 3—Preparation of(S)-2-hydrazinyl-3-(3-hydroxy-4-((phosphonooxy)methoxy)phenyl)-2-methylpropanoicacid (Compound 4) and(S)-2-hydrazinyl-3-(4-hydroxy-3-((phosphonooxy)methoxy)phenyl)-2-methylpropanoicacid (Compound 5)

(S)-benzyl2-benzyl-2-(1-(benzyloxy)-3-(3-(benzyloxy)-4-(((bis(benzyloxy)phosphoryl)oxy)methoxy)phenyl)-2-methyl-1-oxopropan-2-yl)hydrazinecarboxylate,Compound 3, (240 mg, 0.261 mmol), 10 mL tetrahydrofuran and 5 mL waterwere added to 20% Pd(OH)2/C, wet (50 mg, 0.036 mmol) in a 50 ml pressurebottle. The mixture was stirred for 1 hour at 50 psi and roomtemperature. The reaction mixture was filtered. The filtrate was mixedwith water, extracted with methyl t-butyl ether twice. The aqueous phasewas dried by a lyophilizer. The concentrate was purified by RP-HPLC(0-10% 0.1% formic acid/acetonitrile in 0.1% formic acid/water onKromacil Phenyl 3.0 cm ID×25 cm, 5u column). The two isomers wereseparated. The fractions collected were combined respectively, and driedby a lyophilizer to afford Compound 4 and Compound 5, each as a loosewhite solid.

Compound 4(16.5 mg, 16.1%): ¹H NMR (501 MHz, DMSO-d₆) δ 6.94 (d, J=8.1Hz, 1H), 6.62 (d, J=2.1 Hz, 1H), 6.54 (dd, J=8.1, 2.1 Hz, 1H), 5.28 (d,J=14.6 Hz, 2H), 2.86 (d, J=13.6 Hz, 1H), 2.78 (d, J=13.6 Hz, 1H), 1.26(s, 3H). MS (ESI+) 337.0

Compound 5 (30.9 mg, 30.2%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.00 (s, 1H),6.68 (m, 2H), 5.32 (m, 2H), 2.91-2.77 (m, 2H), 1.26 (s, 3H). MS (ESI+)337.0

Example 11 Synthesis of Carbidopa 4′-Monophosphate Methyl Ester

Carbidopa 4′-monophosphate methyl ester was prepared as shown in Scheme11 below:

Step 1

A 100 mL round bottom flask was charged with(S)-3-(3-(benzyloxy)-4-((bis(benzyloxy)phosphoryl)oxy)phenyl)-2-(1,2-bis((benzyloxy)carbonyl)hydrazinyl)-2-methylpropanoicacid (3.03 g, 3.59 mmol) (1), DCC (0.889 g, 4.31 mmol), 25 mL ofmethanol, and a stir bar. To this stirring mixture,4-(dimethylamino)pyridine (88 mg, 0.720 mmol) was added in one portionand the reaction was stirred for an additional 48 h. After this time,the solvent was removed on a rotary evaporator leaving a light yellowresidue. The residue was suspended in acetonitrile (40 mL) and stirredat 5° C. for 2 h. The suspension was then filtered through a silica gelpad, eluting with 400 mL of acetonitrile. Removal of the acetonitrile ona rotary evaporator gave 94% yield of a pale yellow oil, which was useddirectly in the next step. LC/MS [M+H]: 859.40.

Step 2

A 150-ml Parr reactor was charged with 5% Pd/C (0.794 mg, 3.36 mmol).The catalyst was slurried in water (4.83 ml) and 5 wt % aq sodiumbicarbonate (5.61 ml, 3.36 mmol). To this slurry was added atetrahydrofuran (29 ml) solution of (S)-dibenzyl1-(3-(3-(benzyloxy)-4-((bis(benzyloxy)phosphoryl)oxy)phenyl)-1-methoxy-2-methyl-1-oxopropan-2yl)hydrazine-1,2-dicarboxylate (2.89 g, 3.36 mmol) (2). The reactor wassealed and purged with argon (4×40 psig), then H₂ (4×50 psig). Thereactor was then re-pressurized to 50 psig of H₂ and stirred at ambienttemperature for 60 min. After this time, the biphasic reaction mixturewas filtered through Celite® diatomaceous earth, using water (2.2 mL) torinse and filter the remnants in the reactor. The biphasic mixture wasdiluted with MTBE (8 ml), stirred for 5 min, and poured into aseparatory funnel. The aqueous layer was separated and washed with DCM(3×30 mL). The aqueous layer was collected and dried on a lyophilizer togive 68% yield of compound 3 as an off-white solid. ¹H NMR (400 MHz,D₂O): δ 1.46 (s, 3H), 2.92 (d, J=12 Hz, 1H), 3.05 (d, J=0.12 Hz, 1H),3.79 (s, 3H), 6.65-6.72 (m, 2H), 7.11 (d, J=8.0 Hz, 1H).

Example 12 Phosphate Prodrug Stability Studies

1-Day Stability Studies

The L-dopa phosphate prodrugs and the carbidopa phosphate prodrugs wereevaluated in a stability study. Aqueous solutions of the prodrugs (80μg/mL) were monitored over a range of pH values at ambient storageconditions through one day to demonstrate feasibility of dosing over thecourse of infusion. Table 12-A below reports the results of this studywhich confirm that the prodrugs have good stability at room temperatureover a one day period.

TABLE 12-A Stability Study (Prodrugs) % Remaining Compound pH After OneDay L-dopa 3′-phosphate 7.0 >99% L-dopa 4′-phosphate 7.0 >99% L-dopa3′,4′-diphosphate 7.0 >99% Carbidopa 3′-phosphate 6.5 >94% Carbidopa4′-phosphate 6.8 >98% Carbidopa 3′,4′-diphosphate 6.8 >97%

In addition, a solution combining the diphosphates of each compound(L-dopa 3′,4′-diphosphate at 35 mg/mL and carbidopa 3′,4′-diphosphate at8.7 mg/mL) was monitored over one day at room temperature. This samplewas purged with nitrogen to remove oxygen. Table 12-B below reports theresults of this study which confirm good stability for the combinationsolution at room temperature with nitrogen purging over a one dayperiod.

TABLE 12-B Stability Study (Diphosphate Combination) % RemainingCompound pH After One Day L-dopa 3′,4′-diphosphate 6.2 >99% Carbidopa3′,4′-diphosphate >99%7-Day Stability Study

In addition, a solution combining the L-dopa 4′-monophosphate at 200mg/mL and carbidopa 4′-monophosphate at 50 mg/mL was monitored over 7days at room temperature. These samples were prepared with and withoutpurging with nitrogen to remove oxygen. Table 12-C below reports theresults of this study which confirm good stability for the combinationsolution at room temperature over 7 days.

TABLE 12-C Stability Study (4′ Monophosphate Combination) Purged or Non-% Remaining Compound pH Purged After 7 Days L-dopa 4′-monophosphate 7.4Nitrogen Purged >99% Carbidopa 4′-monophosphate >99% L-dopa4′-monophosphate Non-Purged >99% Carbidopa 4′-monophosphate >97%

Example 13 Phosphate Prodrug Solubility Studies

The L-dopa phosphate prodrugs and the carbidopa phosphate prodrugs wereevaluated in a solubility study. The solubility values of the phosphateprodrugs in water under ambient conditions were determined by visualassessment. Table 13-A reports the results of the study, including themeasured values for L-dopa and carbidopa.

TABLE 13-A Solubility Study Solid State Solubility Compound pH Form(mg/mL) L-dopa 4-7 Crystalline <6 L-dopa 3′-phosphate 7.0Crystalline >161 L-dopa 4′-phosphate 7.4 Crystalline >400 L-dopa3′,4′-diphosphate 5.5 Amorphous >330 Carbidopa 4-7 Crystalline <4monohydrate Carbidopa 3′-phosphate 7.1 Amorphous >96 Carbidopa4′-phosphate 7.4 Amorphous >200 Carbidopa 3′,4′-diphosphate 5.5Amorphous >247

FIG. 1 shows increased solubility of L-dopa 4′-monophosphate andcarbidopa 4′-monophosphate compared to L-dopa and carbidopa.

Example 14 Hydrazine Release Studies

Solutions combining the L-dopa 4′-monophosphate at 50 mg/mL andcarbidopa 4′-monophosphate at 12.5 mg/mL were monitored for the releaseof hydrazine over 7 days. These solutions were prepared from pH 5 to pH8, were purged with nitrogen to remove oxygen and were held at roomtemperature. It was found that there was a large reduction in hydrazinerelease at a pH of about 7.4, as shown in Figure. 2. The amount ofhydrazine released from Duopa® was also determined for comparisonpurposes. As shown in FIG. 3, the 4:1 ratio of a solution L-dopa4′-monophosphate and carbidopa 4′-monophosphate at a pH of about 7.4unexpectedly has a much lower release of hydrazine compared to Duopa®.

Example 15 In Vitro Bioconversion Studies

The in vitro bioconversion of the L-dopa phosphate prodrugs to L-dopaand the carbidopa phosphate prodrugs to carbidopa was evaluated inseveral studies. In brief, the L-dopa and carbidopa phosphate prodrugs(2.5 ug/mL) were incubated with tissue homogenate or fractions fromrats, mini-pigs, or human, including blood, skin homogenate (3 mg/mL),liver microsomes (1 mg/mL), liver S9 fraction (1 mg/mL), kidney S9fraction (1 mg/mL), and intestine S9 fractions (1 mg/mL). The reactionmixtures were incubated at 37° C. for 5 to 6 time points within 1 to 2hours. At the end of each time point, the reaction mixtures werequenched by 2 to 3 volumes of 5% trichloroacetic acid in water. Afterquenching, the mixtures were centrifuged at 3000 rpm for 20 minutes, andthe supernatants were analyzed by LC-MS for quantitation of the prodrug,L-dopa or carbidopa. The in vitro bioconversion was assessed bymonitoring both time-dependent depletion of the prodrug and theformation of the corresponding L-dopa or carbidopa.

Table 15-A below reports the results of the study in blood. In blood,all four mono-phosphate prodrugs were rapidly dephosphorylated in rat,mini-pig, and human, with corresponding time-dependent formation ofL-dopa or carbidopa. In general, the t_(1/2) is the shortest inmini-pig, followed by rat, and then human. The diphosphate prodrugs ofcarbidopa and L-dopa were also rapidly dephosphorylated in rat bloodwith a t_(1/2) of 53 minutes and 6 minutes, respectively, withcorresponding formation of L-dopa or carbidopa. Dephosphorylation of thediphosphate prodrug of L-dopa was slower in human and mini-pig bloodwith a t_(1/2) of 138 minutes and 125 minutes, respectively.Corresponding time-dependent formation of L-dopa was observed in bothmini-pig and human blood incubations. However, the diphosphate prodrugof carbidopa was not dephosphorylated in mini-pig and human blood. Noformation of carbidopa was observed in the blood incubations.

TABLE 15-A In Vitro Bioconversion Study (Blood) L-Dopa or CarbidopaProdrug Species T_(1/2) (min.) Formation 3′-monophosphate Human 28 Yesprodrug of L-dopa Rat 20.6 Yes Mini-pig 8.8 Yes 4′-monophosphate Human30.9 Yes prodrug of L-dopa Rat 15 Yes Mini-pig 8.8 Yes3′,4′-disphosphate Human 138 Yes prodrug of L-dopa Rat 6 Yes Mini-pig125 Yes 3′-monophosphate Human 58 Yes prodrug of carbidopa Rat 20.5 YesMini-pig 8.9 Yes 4′-monophosphate Human 64.7 Yes prodrug of carbidopaRat 14.9 Yes Mini-pig 8.8 Yes 3′,4′-diphosphate Human stable No prodrugof carbidopa Rat 53 Yes Mini-pig stable No

Table 15-B below reports the results of the study in skin homogenates.In skin homogenates, the four mono-phosphate prodrugs were slowlydephosphorylated with a t½ ranging from 114 minutes to 992 minutes, withcorresponding formation of L-dopa or carbidopa. The two diphosphateprodrugs were stable in skin homogenates of rat, mini-pig, and human. Noformation of L-dopa or carbidopa was observed in the incubations.

TABLE 15-B In Vitro Bioconversion Study (Skin Homogenates) L-Dopa orCarbidopa Prodrug Species T_(1/2) (min.) Formation 3′-monophosphateHuman 673 Yes prodrug of L-dopa Rat 737 Yes Mini-pig 885 Yes4′-monophosphate Human 592 Yes prodrug of L-dopa Rat 992 Yes Mini-pig424 Yes 3′,4′-disphosphate Human stable No prodrug of L-dopa Rat stableNo Mini-pig stable No 3′-monophosphate Human 602 Yes prodrug ofcarbidopa Rat 724 Yes Mini-pig 413 Yes 4′-monophosphate Human 138 Yesprodrug of carbidopa Rat 271 Yes Mini-pig 114 Yes 3′,4′-diphosphateHuman stable No prodrug of carbidopa Rat stable No Mini-pig stable No

In human liver microsomes, four prodrugs (3′-phosophate and diphosphateprodrugs of L-dopa, and 4′-phosophate and diphosphate prodrugs ofcarbidopa) were stable without formation of L-dopa or carbidopaobserved.

In liver S9 fractions of rat, mini-pig and human, four prodrugs(4′-phosophate and diphosphate prodrugs of L-dopa, and 4′-phosophate anddiphosphate prodrugs of carbidopa) were stable without formation ofL-dopa or carbidopa observed.

In kidney S9 fractions of rat and human, four prodrugs (4′-phosophateand diphosphate prodrugs of L-dopa, and 4′-phosophate and diphosphateprodrugs of carbidopa) were stable without formation of L-dopa orcarbidopa observed.

Table 14-C below reports the results of the study in intestinal S9fractions. In intestinal S9 fractions of rat and human, four prodrugs(4′-phosophate and diphosphate prodrugs of L-dopa, and 4′-phosophate anddiphosphate prodrugs of carbidopa) were rapidly dephosphorylated. Thet_(1/2) appeared to be shorter in human intestinal S9 than in ratintestinal S9. Corresponding time-dependent formation of L-dopa orcarbidopa was observed in the incubations of prodrugs with rat or humanintestinal S9 fractions. The results suggest significant phosphataseactivities in rat and human intestine.

TABLE 15-C In Vitro Bioconversion Study (Intestinal S9 Fractions) L-Dopaor Carbidopa Prodrug Species T_(1/2) (min.) Formation 4′-monophosphateHuman 34.3 Yes prodrug of L-dopa Rat 158 Yes 3′,4′-disphosphate Human 92Yes prodrug of L-dopa Rat 54.2 Yes 4′-monophosphate Human 24.1 Yesprodrug of carbidopa Rat 73.6 Yes 3′,4′-diphosphate Human 31.5 Yesprodrug of carbidopa Rat 79 Yes

Example 16 Pharmacokinetic Studies in Rats

The in vivo conversion of the L-dopa phosphate prodrugs to L-dopa andthe carbidopa phosphate prodrugs to carbidopa was evaluated in a ratpharmacokinetics study in which the prodrug was administeredintravenously or subcutaneously to the rat. For comparison, a ratpharmacokinetics study with L-dopa and carbidopa was conducted to helpassess the in vivo conversion of the prodrugs. The study design andmeasured exposures of L-dopa and carbidopa are summarized in Tables 16-Aand 16-B, respectively. In brief, groups of three male Sprague-Dawleyrats were given (1) L-dopa and carbidopa in aqueous solution, or (2) theindividual prodrug in aqueuous solution intravenously or subcutaneously.Blood samples were collected at multiple time points over 24 hours intoa collection tube containing NaAsO₄, EDTA, and ascorbic acid. Plasma wasseparated from blood and subjected to protein precipitation with 2 to 3volumes of 5% trichloroacetic acid in water, followed by centrifugation.The supernatants were subjected to LC-MS analysis for quantitation ofprodrug, L-dopa or carbidopa.

TABLE 16-A In Vivo Exposures in Rats (L-Dopa) Estimated Conversion %(Based Dosing Dose L-dopa AUC_(O-8 h) on L-dopa Dosed Compound Route(mg/kg) (ng · hr/mL) AUC) 3′-monophosphate SC 7.05 645 96 prodrug ofL-dopa IV 7.05 768 66 4′-monophosphate SC 7.05 1280 >100 prodrug ofL-dopa IV 7.05 1540 >100 3′,4′-diphosphate SC 8.5 1480 >100 prodrug ofL-dopa IV 8.5 1700 >100 L-dopa SC 5 669 — IV 5 1170 —

TABLE 16-B In Vivo Exposures in Rats (Carbidopa) Estimated Conversioncarbidopa % (Based on Dosing Dose AUC_(O-8 h) carbidopa Dosed CompoundRoute (mg/kg) (ng · hr/mL) AUC) 3′-monophosphate SC 1.7 605 88 prodrugof IV 1.7 861 100 carbidopa 4′-monophosphate SC 1.7 863 >100 prodrug ofIV 1.7 757 88 carbidopa 3′,4′-diphosphate SC 2.1 615 90 prodrug of IV2.1 808 94 carbidopa Carbidopa SC 1.25 685 — IV 1.25 860 —

By comparison of the in vivo exposures of L-dopa or carbidopa obtainedfrom administration of the prodrugs to those obtained fromadministration of L-dopa or carbidopa alone, in vivo conversions of theprodrugs to the corresponding L-dopa or carbidopa were estimated to begreater than 66%.

Example 17 L-Dopa Diphosphate/Carbidopa Diphosphate Ratio Study

The effect of various dose ratios of the carbidopa diphosphate to theL-dopa diphosphate on steady state levels of L-dopa was evaluated in arat pharmacokinetics study. In the study, the rats received a 16-hoursubcutaneous infusion of a combination of L-dopa diphosphate (fixeddose) and carbidopa diphosphate (various doses) together in an aqueoussolution. In brief, groups of three male Sprague-Dawley rats were givena combination of L-dopa diphosphate and carbidopa diphosphate withdifferent dose ratios. Table 17-A provides a summary of the studydesign. Rats were initially given subcutaneous bolus doses over oneminute at the dose volume of 1 mL/kg. After 1.5 hours, continuousinfusion doses were administrated over the following 14.5 hours at thedose volume of 10 mL/kg. Blood samples were collected at 0.25, 0.5, 1,6, 16 and 20 hours post bolus dose. The blood samples were processed inthe same way as described in Example 16. Separate aliquots of bloodsamples were collected for measurement of hydrazine.

TABLE 17-A Study Design of Prodrug Ratio Study in Rats SubcutaneousSubcutaneous Bolus Dose Infusion Dose (mg/Kg) over 1 min (mg/kg) over14.5 h L-Dopa Carbidopa L-Dopa Carbidopa Dose Diphosphate DiphosphateDiphosphate Diphosphate Group Prodrug Prodrug Prodrug Prodrug LD 15 0 750 alone LD 50:1 15 0.3 75 1.5 LD 15:1 15 1 75 5 LD 7.5:1 15 2 75 10 LD4:1 15 3.75 75 18.75 LD 1:1 15 15 75 75

Both L-dopa and carbidopa levels were well maintained during thecontinuous infusion period between 1 hour and 16 hours in each dosegroup. FIG. 4 provides a time-concentration profile for L-dopa bloodlevels after administration of the combination of diphosphate prodrugsat different ratios. FIG. 5 provides a time-concentration profile forcarbidopa blood levels after administration of the combination ofdiphosphate prodrugs at different ratios.

Table 17-B below reports the measured steady-state blood levels ofL-dopa (“LD”) and carbidopa (“CD”). FIG. 6 presents the same datagraphically. The ratio of the L-dopa diphosphate to the carbidopaphosphate had a significant effect on the steady state level of L-dopa.For example, after administration of the L-dopa diphosphate alone, meanplasma concentration of L-dopa at 6 hours (C_(6h)) was 0.164 μg/mL. Whena combination of L-dopa diphosphate and carbidopa diphosphate wasadministered at the dose ratio of 50:1, mean plasma concentration ofL-dopa at 6 hours (C_(6h)) increased to 0.55 μg/mL. When a combinationof L-dopa diphosphate and carbidopa diphosphate was administered at thedose ratio of 1:1, mean plasma concentration of L-dopa at 6 hours(C_(6h)) further increased to 1.47 μg/mL. In all groups, hydrazinelevels were below the limit of quantitation (0.5 ng/mL).

TABLE 17-B Steady-State Levels of L-Dopa and Carbidopa (DifferentProdrug Ratios) LD concentration at 6 h CD concentration at 6 h Group(μg/mL) (μg/mL) LD alone 0.164 0 LD 50:1 0.55 0.006 LD 15:1 0.52 0.03 LD7.5:1 1 0.103 LD 4:1 0.99 0.175 LD 1:1 1.47 0.734

Example 18 L-Dopa 4′-Monophosphate/Carbidopa 4′-MonophosphatePharmacokinetic Studies in Rats

The effect of a 4:1 ratio of L-dopa 4′-monophosphate to carbidopa4′-phosphate on steady state levels of L-dopa was evaluated in a ratpharmacokinetics study.

16-Hour Subcutaneous Infusion

In this study, a combination L-dopa 4′-monophosphate and the carbidopa4′-monophosphate together in an aqueous solution at a dose ratio of 4:1was initially administrated to the rats via subcutaneous bolus at thedose of 60/14 mg/kg over 1 min. After 1.5 hours, the combination wasdosed again via continuous infusion at a dose of 300/71 mg/kg over next14.5 hours. Blood samples were collected at 0, 0.25, 1, 6, 16, and 24hours post dose. The blood samples were processed in the same way asdescribed in Example 15. Separate aliquots of blood samples werecollected for measurement of hydrazine. FIG. 7 provides atime-concentration profile for L-dopa and L-dopa 4′-monophosphate bloodlevels after administration of the combination of 4′-monophosphateprodrugs at a 4:1 ratio. As shown in FIG. 7, continuous subcutaneousinfusion of 4:1 L-dopa 4′-monophosphate and carbidopa 4′-monophosphatedelivered high systematic levels of L-dopa (e.g., ˜10 μg/mL), whichmeets and/or exceeds the plasma levels (e.g., ˜3 μg/mL) achieved withDuopa®, as shown in FIG. 8. Steady state concentration of ˜1 μg/mL wasmaintained over the infusion period for carbidopa. Exposures of theremaining L-dopa 4′-monophosphate and carbidopa 4′-monophosphate were˜22% and ˜8% of levodopa and carbidopa, respectively. The doses werewell tolerated in rats, and no hydrazine was detected in rat plasmasamples. FIG. 9 provides a time-concentration profile for carbidopa andcarbidopa 4′-monophosphate blood levels after administration of thecombination of 4′-monophosphate prodrugs at a 4:1 ratio.

7-Day 24-Hour Subcutaneous Infusion

In this study, the rat received a 24-hour subcutaneous infusion of acombination of the L-dopa (LD) 4′-monophosphate and the carbidopa (CD)4′-monophosphate together in an aqueous solution at a dose ratio of 4:1for 7 days. Table 18-A below reports the measured steady-stateconcentration of levodopa at various amounts of L-dopa 4′-monophosphateand carbidopa 4′-monophosphate in a 4:1 ratio.

TABLE 18-A Steady-State Concentration Levels of L-Dopa Prodrug DoseLD-4′- Phosphate/CD-4′-phosphate (mg/kg) L-Dopa Css (μg/mL) 100/25 2.18± 0.3 300/75 9.36 ± 1.9   750/187.5  35.2 ± 13.5

Example 19 L-Dopa Diphosphate and Carbidopa Diphosphate PharmacokineticStudies in Mini-Pigs

The in vivo conversion of the carbidopa diphosphate to carbidopa wasevaluated in a mini-pig pharmacokinetics study in which the prodrug wasadministered in aqueous solution subcutaneously to a group of threemini-pigs. For comparison, a pharmacokinetics study with carbidopa alsowas conducted to help assess the in vivo conversion of the carbidopaprodrugs. Table 19-A reports the measured carbidopa exposures. Theestimated in vivo conversion of the carbidopa diphosphate to carbidopawas approximately 100%, based on the carbidopa exposures.

TABLE 19-A In Vivo Carbidopa Exposures in Mini-Pig Carbidopa EstimatedConversion Dosed Dosing Dose AUC_(O-8 h) (Based on Compound Route(mg/kg) (ng · hr/mL) Carbidopa AUC) 3′,4′- SC 8.5 6870 100 diphosphateprodrug of carbidopa Carbidopa SC 2 1610 —

The effect of various dose ratios of the carbidopa diphosphate to theL-dopa diphosphate on steady state levels of L-dopa was evaluated in amini-pig pharmacokinetics study. In the study, the mini-pig received a16-hour subcutaneous infusion of a combination of the L-dopa diphosphateand the carbidopa diphosphate together in an aqueous solution at aspecified dose ratio. A wash-out period followed each dose ratio. Thestudy design is summarized in Table 19-B below and was similar to thedesign of the previously described rat study except that there were noinitial subcutaneous bolus doses. Blood samples were collected at 1, 2,4, 6, 8, 10, 14, 16, and 24 hours post dose. The blood samples wereprocessed in the same way as described in Example 12. Separate aliquotsof blood samples were collected for measurement of dopamine.

TABLE 19-B Study Design of Prodrug Ratio Study in Mini-Pigs SubcutaneousInfusion Dose (mg/kg) over 16 h Carbidopa Dose Group L-Dopa DiphosphateProdrug Diphosphate Prodrug LD alone 45.9 0 LD 15:1 45.9 3.06 LD 7.5:145.9 6.12 LD 4:1 45.9 11.5

FIG. 10 provides a time-concentration profile for L-dopa blood levelsafter administration of the combination of diphosphate prodrugs atdifferent ratios. No dopamine was detected in the mini-pigs blood plasmasamples.

Example 20 15:1 L-Dopa 4′-Monophosphate/Carbidopa 4′-MonophosphatePharmacokinetic Studies in Mini-Pigs

The effect of a 15:1 ratio of L-dopa 4′-monophosphate to carbidopa4′-phosphate on steady state levels of L-dopa was evaluated in amini-pig pharmacokinetics study.

In this study, the pig received a 16-hour subcutaneous infusion of acombination of the L-dopa 4′-monophosphate and the carbidopa4′-monophosphate together in an aqueous solution at a dose ratio of 15:1without an initial bolus dose. The doses were 48/3.2 mg/kg for L-dopa4′-monophosphate and the carbidopa 4′-monophosphate, respectively. Bloodsamples were collected at 1, 3, 6, 8, 10, 14, and 24 hours post dose.The blood samples were processed in the same way as described in Example12. Separate aliquots of blood samples were collected for measurement ofhydrazine. Table 20-A provides a summary of measured exposures of L-dopa4′-monophosphate and L-dopa in the mini-pigs.

TABLE 20-A L-dopa Prodrug Levodopa Minipig # C_(max) T_(max) AUC_(0-t)C_(max) T_(max) AUC_(0-t) 1 814 3.0 7110 4320 14 63000 2 681 3.0 64506030 10 84300 3 689 6.0 6670 6180 14 85400 Mean 728 4.0 6740 5510 1377600 SEM 43.1 1.0 194 597 1.3 7270 C_(max) [ng/mL]; T_(max) [hr];AUC_(0-t) [ng * hr/mL];

FIG. 11 provides a time-concentration profile for L-dopa and L-dopa4′-monophosphate blood levels after administration of the combination of4′-monophosphate prodrugs at a 15:1 ratio. As shown in FIG. 11,continuous subcutaneous infusion of 15:1 L-dopa 4′-monophosphate andcarbidopa 4′-phosphate delivered high systematic levels of L-dopa (e.g.,˜5.5 μg/mL), which meets and/or exceeds the plasma levels (e.g., ˜3μg/mL) achieved with Duopa®, as shown in FIG. 8. Plasma concentration oflevodopa increased over time and was close to steady state at ˜10 hourspost dose. Steady-state levodopa plasma concentration was achieved at˜5.5 μg/mL. Exposure of the remaining the L-dopa 4′-monophosphate was˜10% of the levodopa exposure. Carbidopa plasma concentration reachedsteady-state at ˜3 hours post dose with a steady-state concentration of˜0.2 μg/mL. Exposure of the remaining the carbidopa 4′-monophosphate was˜22% of the carbidopa exposure. The doses were well tolerated inmini-pigs, and no hydrazine was detected in mini-pig plasma samples.FIG. 12 provides a time-concentration profile for carbidopa andcarbidopa 4′-monophosphate blood levels after administration of thecombination of 4′-monophosphate prodrugs at a 15:1 ratio.

Example 21 L-Dopa 4′-Monophosphate and Carbidopa 4′-MonophosphatePharmacokinetic Studies in Dogs

In this study, the dog received a 24-hour subcutaneous infusion of acombination of the L-dopa (LD) 4′-monophosphate and the carbidopa (CD)4′-monophosphate together in an aqueous solution at a dose ratio of 4:1.Table 21-A below reports the measured steady-state concentration oflevodopa (L-dopa) at various amounts of the L-dopa 4′-monophosphate andcarbidopa 4′-monophosphate in a 4:1 ratio. There was no mortality andall dogs survived to the end of the study. The (LD) 4′-monophosphate andthe carbidopa (CD) 4′-monophosphate drugs were well tolerated. Test itemrelated clinical signs in the 400/100 mg/kg consisted of emesis in bothdogs, which occurred early during the dosing interval. Clinicalpathology findings in the Levodopa and Carbidopa 4′-monophosphateprodrugs consisted of mildly increased neutrophil and monocyte counts at400/100 mg/kg; mildly decreased triglycerides for animals administered≧200/50 mg/kg; mildly increased bilirubin for animals administered≧200/50 mg/kg; increased urine specific gravity at all doses; minimallyincreased urine phosphorus to creatinine ratio and fractional excretionof phosphorus at 400/100 mg/kg. Conclusions: Administration of L-dopa(LD) 4′-monophosphate and the carbidopa (CD) 4′-monophosphate at dosesof up to 400/100 mg/kg resulted in no adverse findings. This resulted ina Levodopa concentration of 18.3 μg/mL and a Carbidopa concentration of2.88 μg/mL.

TABLE 21-A Steady-State Concentration Levels of L-Dopa Prodrug DoseLD-4′- monophosphate/CD-4′- Carbidopa Css monophosphate (mg/kg) L-DopaCss (μg/mL) (μg/mL) 100/25 2.13 0.673 200/50 5.08 1.47  400/100 18.32.88

Example 22 Phosphorus Load

When rats were administered L-dopa diphosphate/carbidopa diphosphateprodrug composition (i.e., diphosphate composition), there was anincrease in serum phosphate at doses ≧300/75 mg/kg/day. This elevationin serum phosphate did not occur in rats administered L-dopa4′-monophosphate/carbidopa 4′-monophosphate composition (i.e.,monophosphate composition) at doses of up to 750/187.5 mg/kg/day.

Example 23 Safety and Tolerability

Local irritation and pain at the injection site were studied.

Local Tolerability:

Pain on injection was evaluated in rabbits using intravenous,paravenous, and subcutaneous bolus injection of LD/CD diphosphate atconcentrations for 200/50 mg/mL. Immediately upon injection and through24 hours of observation there was no indication of injection site painor local tissue irritation. There were no adverse clinical signs ormicroscopic findings indicative of local intolerance in ratsadministered a single SC bolus dose of LD diphosphate at concentrationsup to 125 mg/mL or in minipigs subcutaneously infused LD/CD diphosphatefor 24 hours at 200/50 mg/mL.

In the 7-day SC infusion studies in rats there was no indication ofinfusion site irritation or intolerability for either the LD/CDdiphosphates or the LD/CD monophosphates when infused at 41/10 and75/18.75 mg/mL, respectively for 18 or 24 hours/day, respectively. WhenLD/CD monophosphate (200/50 mg/mL) was subcutaneously infused to dogsfor 24 hours there was no apparent visual irritation at the injectionsite. The cumulative data is supportive of a low risk for pain oninjection or local tissue irritation, when infused at the same site for24 hours.

Rodent Toxicity:

A 7-day IV infusion toxicity study was conducted with L-Dopa andcarbidopa diphosphate prodrugs together in an aqueous solution.Sprague-Dawley rats (n=5/sex/group) were administered dosages of 80/20,240/60 or 720/180 mg/kg for 18 hours per day over 7 consecutive days.Although rats in the 720/180 mg/kg group exhibited an increase in serumphosphorus, other than body weight loss and reductions in foodconsumption there were no adverse clinical signs, clinical pathology orhistopathology findings observed. The L-Dopa disphosphate and carbidopadiphosphate prodrugs dose of 720/180 mg/kg resulted in a levodopa plasmaconcentration of 15.2 μg/mL.

A 7-day SC infusion toxicity study was also conducted with L-Dopa andcarbidopa diphosphate prodrugs together in an aqueous solution.Sprague-Dawley rats (n=5/sex/group) were administered dosages of 100/25,300/75 or 750/187.5 mg/kg for 18 hours per day over 7 consecutive days.Although male rats in the 300/75 and male and female rats in the750/187.5 mg/kg groups exhibited an increase in serum phosphorus, withexception of body weight loss and reductions in food intake there wereno adverse clinical signs, clinical pathology or histopathology findingsobserved. The dose of 750/187.5 mg/kg resulted in a levodopa plasmaconcentration of 19.6 μg/mL.

A 7-day SC infusion toxicity study was also conducted with L-Dopa andcarbidopa mixed monophosphate together in an aqueous solution. MaleSprague-Dawley rats (n=4 or 5/group) were administered dosages of100/25, 300/75 or 750/187.5 mg/kg for 24 hours per day over 7consecutive days. Rats in the 750/187.5 mg/kg group exhibited clinicalsigns that included aggressive behavior and increased activity. Thefindings were sufficiently pronounced that they impacted the SC catheterplacement and patency and that some animals were removed from studyprior to completing the full dose schedule. Mean body weights at the endof the study in the 300/75 mg/kg groups were decreased by 18% relativeto the start of dosing on day 1. There were no significant effects onserum or urinary phosphate and there were no adverse clinical pathologyor histopathology findings. The levodopa plasma concentration was 9.4μg/mL in the 300/75 mg/kg group.

Example 24 Human Prediction of Steady State Exposures of L-dopa andL-dopa 4′-Monophosphate, Carbidopa and Carbidopa 4′-Monophosphate asWell as Phosphorus Daily Load

Key factors for human prediction include:

-   -   1) linear human pharmacokinetics;    -   2) bioconversion ratios of prodrugs in human are estimated at        the mean bioconversion ratios observed in preclinical animals        (0.9 for L-dopa 4′-monophosphate and 0.7 for Carbidopa        4′-monophosphate);    -   3) high bioavailability (F) of monophosphate prodrugs after        subcutaneous (SC) dosing (0.75 for L-dopa 4′-monophosphate and        0.65 for Carbidopa 4′-monophosphate);    -   4) phosphate release from prodrug is complete after SC dosing.        Projected PK parameters for monophosphate prodrug and active        drugs are shown in Table 24-A.

TABLE 24-A Projected human PK parameters for monophosphate prodrugs andactive drugs CLp (l/hr) SC F Bioconversion ratio Value Range Value Rangefrom to Value Range L-dopa 4′- 100 2-fold 0.75 0.7-1   L-dopa 4′- 0.90.8-1 monophosphate monophosphate to levdopa levodopa 24 2-foldCarbidopa 4′- 141 2-fold 0.65 0.5-0.9 Carbidopa 4′- 0.7 0.5-1monophosphate monophosphate to carbidopa carbidopa 18 2-fold CLp, plasmaclearance; SC: subcutaneous; F: bioavailability

Using the point estimate values, a simulation of 150/38 mg/hr (L-dopa4′-monophosphate/Carbidopa 4′-monophosphate) continuous SC infusionprovides a steady state concentration (Css) of levodopa at 3000 ng/ml,with phosphorus load of 427 mg/day as shown Table 24-B.

TABLE 24-B Point estimate of PK parameters of L-dopa 4′-monophosphate,levodopa, Carbidopa 4′-monophosphate and carbidopa. Dose rate L-dopa 4′-monophosphate/ Css Css CLp Carbidopa-4′- Css L-dopa 4′- Css Carbidopa4′- Levodopa monophosphate phosphorus load levodopa monophosphateCarbidopa monophosphate (L/hr) (mg/day) (mg/day) (ng/ml) (ng/ml) (ng/ml)(ng/ml) 24 3600/912 427 3000 1200 722 186

The aqueous solubility of L-dopa 4′-monophosphate can reach as highas >300 mg/mL. One 20-mL vial of dose solution per day coulddeliver >6000 mg per day of L-dopa 4′-monophosphate, which could deliverthe Css of levodopa of >5 ug/mL assuming linear human pharmacokinetics.

Example 25 Crystalline Carbidopa-4′-Monophosphate Trihydrate Preparation

95 mg sample of amorphous carbidopa-4′-monophosphate was weighed in a 8mL vial and dissolved with 200 μl of water. 500 μL of isopropyl alcoholwas added after all the solid was dissolved. The solution turned cloudyafter the addition of the isopropanol. The cloudy suspension was stirredusing a magnetic stir bar at room temperature for 15 min. Then 200 μL ofIPA was added. The slurry was stirred for an hour and then filtered. Thewet cake was washed with 1 mL of IPA. The solid was air-dried overnightand then analyzed by powder x-ray diffraction (PXRD) the following day.The PXRD pattern for crystalline carbidopa-4′-monophosphate trihydrateis shown in FIG. 17.

Example 26a Crystalline Carbidopa-4′-Monophosphate Dihydrate Preparation

420 mg of carbidopa-4′-monophosphate trihydrate was weighed into a 20 mLvial. 8.4 mL of n-butanol was added to the vial, and the content wasstirred overnight at 30° C. with a magnetic stir bar. A wet cake samplewas isolated and analyzed by PXRD. The PXRD pattern for crystallinecarbidopa-4′-monophosphate dihydrate is shown in FIG. 18.

Example 26b Crystalline Carbidopa-4′-Monophosphate Dihydrate Preparation

103 mg of amorphous carbidopa-4′-monophosphate was weighed into a 4 mLvial. 200 μl of water was added. After all the solids were dissolved,500 μl of isopropyl alcohol was added and the solution was stirred atroom temperature using a magnetic stir bar. 30 min later solids wereobserved in the vial. At that point 200 μl of IPA was added and theslurry was stirred for 30 more min. The solids were then isolated and aPXRD pattern of the wet cake was analyzed. The PXRD pattern of the wetcake was consistent with the PXRD pattern shown in FIG. 18.

Example 27 Crystalline Carbidopa-4′-Monophosphate Dehydrate Preparation

About 10 mg of carbidopa-4′-monophosphate trihydrate was loaded on atared aluminum pan of the DVS Advantage (Surface Measurement SystemsLtd, Alperton, United Kingdom). The sample was subjected to thefollowing humidity conditions at 25° C.: 30-0-90-0-30% relative humidity(RH) in 10% RH intervals. For each step, the dm/dt (change of mass overchange in time) criteria was 0.001% over 5 minutes and a minimum dm/dttime of 30 minutes and a maximum dm/dt of 120 minutes. The nitrogen flowrate during analysis 200 was cc/min. The post-DVS sample was kept at 30%RH prior to PXRD analysis. The PXRD pattern for crystallinecarbidopa-4′-monophosphate dehydrate is shown in FIG. 19.

Example 28 Crystalline L-Dopa-3′-Monophosphate Preparation

Crystalline L-dopa-3′-monophosphate was prepared according to Example 1(Steps 1, 2, 3, 4b, 5b) described above. The PXRD pattern forcrystalline L-dopa-3′-monophosphate is shown in FIG. 15.

Example 29 Crystalline L-Dopa-4′-Monophosphate Anhydrate (i) Preparation

Crystalline L-dopa-4′-monophosphate anhydrate (i) was prepared accordingto Example 5 described above. The PXRD pattern for crystallineL-dopa-4′-monophosphate anhydrate (i) is shown in FIG. 13.

Example 30 Crystalline L-Dopa-4′-Monophosphate Anhydrate (ii)Preparation

204 mg of L-dopa-4′-monophosphate anhydrate (i) was weighed in a 4-mLvial. 1 mL of dimethyl sulfoxide and 1 mL of water was added. Theresulting slurry was stirred at 24° C. The solid was then filtered,air-dried and analyzed by PXRD. The PXRD pattern for crystallineL-dopa-4′-monophosphate anhydrate (ii) is shown in FIG. 14.

Example 31 Crystalline Carbidopa-3′-Monophosphate (i) Preparation

100 mg of amorphous carbidopa-3′-monophosphate was weighed in a 4 mLvial. 300 μl of water was added. Once the solid was dissolved, 600 μl ofisopropanol was added. The resulting clear solution was stirred with amagnetic stir bar at room temperature overnight until solids came out ofsolution. 300 μl of isopropanol was added and the suspension was stirredfor 15 min. The suspension was then filtered and the resulting solid wasdried in a vacuum oven at room temperature. The dried solid was analyzedby PXRD. The PXRD pattern for crystalline carbidopa-3′-monophosphate (i)is shown in FIG. 20.

Example 32 Crystalline Carbidopa-3′-Monophosphate (ii) Preparation

25 mg of carbidopa-3′-monophosphate (i) was weighed in a 2 ml vial. 100μl of water was added to dissolve the solid. The vial was placed in aCrystal 16 instrument (Avantium Technologies, Amsterdam, Netherlands)and subjected to the following heat/cool cycle while stirring with amagnetic stir bar: ramp at 10° C./h to 50° C., hold for 4 h, ramp at 20°C./hr to −15° C., hold for 4 h, ramp at 10° C./h to 50° C., hold for 4h, ramp to −15° C. at 10° C./h, hold for 4 h, ramp to 50° C. at 10°C./h, hold for 4 h, ramp to −15° C. at 5° C./h, hold for 4 h, ramp to25° C. at 10° C./h and hold until PXRD analysis. The solid was thenfiltered and the wet cake was analyzed by PXRD. The PXRD pattern forcrystalline carbidopa-3′-monophosphate (ii) is shown in FIG. 21.

Example 33 Crystalline Carbidopa-3′,4′-Diphosphate Sodium SaltPreparation

46 mg of amorphous carbidopa 3′,4′-diphosphate and 5.6 mg of sodiumhydroxide pellets was dissolved in 500 μL of dimethyl sulfoxide and 200μL of water. 400 mg of IPA was added. The solution was then heated to35° C., and then allowed to cool to room temperature. The solution wasstirred with a magnetic stir bar until needles precipitated out. Thesolid was then filtered out and analyzed by PXRD. The PXRD pattern forcrystalline carbidopa-3′,4′-diphosphate sodium salt is shown in FIG. 22.

Example 34 Crystalline L-Dopa-3′,4′-Diphosphate Trihydrate Preparation

62.1 mg of amorphous L-dopa 3′,4′-diphosphate was weighed in a 2 mlvial. 200 μl of water was added to dissolve the solid. The vial wasplaced in a Crystal 16 instrument (Avantium Technologies, Amsterdam,Netherlands) and subjected to the following heat/cool cycle whilestirring with a magnetic stir bar: ramp at 10° C./h to 50° C., hold for4 h, ramp at 20° C./hr to −15° C., hold for 4 h, ramp at 10° C./h to 50°C., hold for 4 h, ramp to −15° C. at 10° C./h, hold for 4 h, ramp to 50°C. at 10° C./h, hold for 4 h, ramp to −15° C. at 5° C./h, hold for 4 h,ramp to 25° C. at 10° C./h and hold until PXRD analysis. The solid wasthen filtered and the wet cake was analyzed by PXRD. The PXRD patternfor crystalline L-dopa-3′,4′-diphosphate trihydrate is shown in FIG. 16.

Alternatively, ethyl acetate, isopropanol, water-saturated ethylacetate, methyl ethyl ketone, acetone, tetrahydrofuran, toluene,2-methyl THF, dichloromethane, tert-tributylamine, isobutylacetate,1,4-dioxane can also be used as solvents to crystallize outL-dopa-3′,4′-diphosphate trihydrate. The following mixtures of solventsin a 1:1 ratio by volume can be used as well: acetone/water, isopropylacetate/heptane.

X. Further Embodiments

Embodiment 1. A pharmaceutical combination comprising a first compoundcorresponding in structure to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂; and

-   -   a second compound corresponding in structure Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂.

Embodiment 2. The pharmaceutical combination of Embodiment 1, whereinthe first compound is

Embodiment 3. The pharmaceutical combination of Embodiment 1 or 2,wherein the second compound is

Embodiment 4. The pharmaceutical combination of any one of the previousembodiments wherein the first compound or pharmaceutically acceptablesalt thereof, and the second compound or pharmaceutically acceptablesalt thereof are present in separate pharmaceutical compositions or areboth present in the same pharmaceutical composition.

Embodiment 5. The pharmaceutical combination of any one of the previousembodiments, wherein a weight ratio of the first compound orpharmaceutically acceptable salt thereof to the second compound orpharmaceutically acceptable salt thereof is about 1:1 to about 1:50,preferably about 1:2 to about 1:15, preferably about 1:4 to about 1:10,and more preferably about 1:4.

Embodiment 6. The pharmaceutical combination of any one of the previousembodiments, wherein the first compound or pharmaceutically acceptablesalt thereof has a solubility of at least about 200 mg/ml in aqueoussolution at about neutral pH, and the second compound orpharmaceutically acceptable salt thereof has a solubility of at leastabout 400 mg/ml in aqueous solution at about neutral pH.

Embodiment 7. The pharmaceutical combination of any one of the previousembodiments, wherein the combination is an aqueous combination suitablefor intragastric, subcutaneous, intramuscular, intrajejunum, oral,intranasal or intravenous administration.

Embodiment 8. The pharmaceutical combination of any one of the previousembodiments, wherein the combination is an aqueous combination suitablefor subcutaneous administration.

Embodiment 9. The pharmaceutical combination of any one of the previousembodiments, wherein the first compound is a compound corresponding instructure to Formula (I-a):

or a pharmaceutically acceptable salt thereof; and the second compoundis a compound corresponding in structure to Formula (II-a):

or a pharmaceutically acceptable salt thereof.

Embodiment 10. The pharmaceutical combination of any one of the previousembodiments, wherein the first compound is a compound corresponding instructure to Formula (I-b):

or a pharmaceutically acceptable salt thereof; and the second compoundis a compound corresponding in structure to Formula (II-a):

or a pharmaceutically acceptable salt thereof.

Embodiment 11. The pharmaceutical combination of any one of the previousembodiments, wherein the first compound is a compound corresponding instructure to Formula (I-c).

or a pharmaceutically acceptable salt thereof; and the second compoundis a compound corresponding in structure to Formula (II-a):

or a pharmaceutically acceptable salt thereof.

Embodiment 12. The pharmaceutical combination of any one of the previousembodiments, wherein the first compound is a compound corresponding instructure to Formula (I-a):

or a pharmaceutically acceptable salt thereof; and the second compoundis a compound corresponding in structure to Formula (II-b):

or a pharmaceutically acceptable salt thereof.

Embodiment 13. The pharmaceutical combination of any one of the previousembodiments, wherein the first compound is a compound corresponding instructure to Formula (I-b):

or a pharmaceutically acceptable salt thereof; and the second compoundis a compound corresponding in structure to Formula (II-b):

or a pharmaceutically acceptable salt thereof.

Embodiment 14. The pharmaceutical combination of any one of the previousembodiments, wherein the first compound is a compound corresponding instructure to Formula (I-c):

or a pharmaceutically acceptable salt thereof; and the second compoundis a compound corresponding in structure to Formula (II-b):

or a pharmaceutically acceptable salt thereof.

Embodiment 15. The pharmaceutical combination of any one of the previousembodiments, wherein the first compound is a compound corresponding instructure to Formula (I-a):

or a pharmaceutically acceptable salt thereof; and the second compoundis a compound corresponding in structure to Formula (II-c):

or a pharmaceutically acceptable salt thereof.

Embodiment 16. The pharmaceutical combination of any one of the previousembodiments, wherein the first compound is a compound corresponding instructure to Formula (I-b):

or a pharmaceutically acceptable salt thereof; and the second compoundis a compound corresponding in structure to Formula (II-c):

or a pharmaceutically acceptable salt thereof.

Embodiment 17. The pharmaceutical combination of any one of the previousembodiments, wherein the first compound is a compound corresponding instructure to Formula (I-c):

or a pharmaceutically acceptable salt thereof; and the second compoundis a compound corresponding in structure to Formula (II-c):

or a pharmaceutically acceptable salt thereof.

Embodiment 18. A method of treating Parkinson's disease in a subject inneed thereof and/or a method of providing rescue therapy in a subjecthaving Parkinson's disease, the method comprising administering to thesubject a therapeutically effective amount of the pharmaceuticalcombination according to any one of the previous embodiments.

Embodiment 19. The method of Embodiment 18, wherein the first compoundand the second compound are administered in separate pharmaceuticalcompositions to the subject, or the first compound and the secondcompound are administered to the subject in the same pharmaceuticalcomposition comprising the first compound and the second compound.

Embodiment 20. The method of Embodiment 18 or 19, wherein the methodcomprises intragastric, subcutaneous, intrajejunum, oral, intranasal,intramuscular or intravenous administration of the first compound andthe second compound.

Embodiment 21. The method of any one of Embodiments 18-20, wherein themethod comprises subcutaneous administration of the first compound andthe second compound.

Embodiment 22. The method of any one of Embodiments 18-21, wherein themethod comprises substantially continuous administration of the firstcompound and the second compound over a period of at least about 12hours.

Embodiment 23. The method of any one of Embodiments 18-22, wherein theweight ratio of the first compound administered to the second compoundadministered is from about 1:1 to about 1:50.

Embodiment 24. The method of any one of Embodiments 18-23, wherein theweight ratio of the first compound administered to the second compoundadministered is from about 1:2 to about 1:15.

Embodiment 25. The method of any one of Embodiments 18-24, wherein theweight ratio of the first compound administered to the second compoundadministered is from about 1:4 to about 1:10.

Embodiment 26. The method of any one of Embodiments 18-25, wherein theweight ratio of the first compound administered to the second compoundadministered is about 1:4.

Embodiment 27. The method of any one of Embodiments 18-26, wherein theweight ratio of the first compound administered to the second compoundadministered is about 1:7.5.

Embodiment 28. The method of any one of Embodiments 18-27, wherein theweight ratio of the first compound administered to the second compoundadministered is about 1:10.

Embodiment 29. The method of any one of Embodiments 18-28, wherein thefirst compound is selected from the group consisting of

and the second compound is selected from the group consisting of

Embodiment 30. The method of any one of Embodiments 18-29 furthercomprising administering another anti-Parkinson's agent to the subject.

Embodiment 31. The method of any one of Embodiments 18-30, wherein thepharmaceutical combination is an aqueous combination.

Embodiment 32. The method of Embodiment 31, wherein the aqueouspharmaceutical combination is administered by intragastric,subcutaneous, intramuscular, intranasal, intrajejunum, oral orintravenous administration.

Embodiment 33. The method of Embodiments 31 or 32, wherein the aqueouspharmaceutical combination is administered by subcutaneousadministration.

Embodiment 34. A compound corresponding in structure to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂

Embodiment 35. The compound or pharmaceutically acceptable salt ofEmbodiment 34, wherein R¹ and R² are each independently selected fromthe group consisting of hydrogen, —P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ isa C₁-C₂-alkyl; R⁶ is hydrogen; and provided that at least one of R¹ andR² is —P(O)(OH)₂ or —R⁵—O—P(O)(OH)₂.

Embodiment 36. The compound or pharmaceutically acceptable salt ofEmbodiment 34 or 35, wherein R¹ and R² are each independently hydrogenor —P(O)(OH)₂; R⁶ is hydrogen; and one of R¹ and R² is —P(O)(OH)₂.

Embodiment 37. The compound or pharmaceutically acceptable salt ofEmbodiment 34 or 35, wherein R¹ and R² are each independently hydrogenor —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₂-alkyl; R⁶ is hydrogen; and providedthat one of R¹ and R² is —R⁵—O—P(O)(OH)₂.

Embodiment 38. The compound or pharmaceutically acceptable salt ofEmbodiment 34, wherein R¹ and R² are each independently hydrogen,—P(O)(OH)₂ or —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₂-alkyl; R⁶ is a C₁-C₂-alkyl;and provided that one of R¹ and R² is —P(O)(OH)₂ or —R⁵—O—P(O)(OH)₂.

Embodiment 39. The compound or salt of any one of Embodiments 34-36,wherein the compound corresponds in structure to Formula (I-a):

Embodiment 40. The compound or salt of any one of Embodiments 34-36,wherein the compound corresponds in structure to Formula (I-b):

Embodiment 41. The compound or salt of any one of Embodiments 35-36,wherein the compound corresponds in structure to Formula (I-c):

Embodiment 42. The compound or salt of any one of Embodiments 34, 35 or37, wherein the compound corresponds in structure to Formula (I-d):

Embodiment 43. The compound or salt of any one of Embodiments 34, 35 or37, wherein the compound corresponds in structure to Formula (I-e):

Embodiment 44. The compound or salt of any one of Embodiments 34 or 38,wherein the compound corresponds in structure to Formula (I-f):

Embodiment 45. A compound corresponding in structure to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂.

Embodiment 46. The compound or salt of Embodiment 45, wherein R³ and R⁴are each independently hydrogen or —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₂-alkyl;R⁶ is hydrogen; and provided that one of R³ and R⁴ is —R⁵—O—P(O)(OH)₂.

Embodiment 47. The compound or salt of Embodiment 45 or 46, wherein thecompound corresponds in structure to Formula (II-d):

Embodiment 48. The compound or salt of Embodiment 45 or 46, wherein thecompound corresponds in structure to Formula (II-e):

Embodiment 49. A pharmaceutical composition comprising a first compoundcorresponding in structure to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂; and a pharmaceutically acceptable carrier.

Embodiment 50. The pharmaceutical composition of Embodiment 49, whereinthe first compound corresponds in structure to Formula (I-a):

Embodiment 51. The pharmaceutical composition of Embodiment 49, whereinthe first compound corresponds in structure to Formula (I-b):

Embodiment 52. The pharmaceutical composition of Embodiment 49, whereinthe first compound corresponds in structure to Formula (I-c):

Embodiment 53. The pharmaceutical composition of any one of Embodiments49-52, wherein the composition further comprises a second compoundcorresponding in structure to Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂.

Embodiment 54. The pharmaceutical composition of Embodiment 53, whereinthe second compound corresponds in structure to Formula (II-a):

Embodiment 55. The pharmaceutical composition of Embodiment 53, whereinthe second compound corresponds in structure to Formula (II-b):

Embodiment 56. The pharmaceutical composition of Embodiment 53, whereinthe second compound corresponds in structure to Formula (II-c):

Embodiment 57. The pharmaceutical composition of any one of Embodiments37-44, wherein the weight ratio of the first compound to the secondcompound is from about 1:1 to about 1:50, preferably from about 1:2 toabout 1:15, even more preferably from about 1:4 to about 1:10.

Embodiment 58. The pharmaceutical composition of any one of Embodiments49-57, wherein the weight ratio of the first compound to the secondcompound is about 1:4.

Embodiment 59. The pharmaceutical composition of any one of Embodiments49-57, wherein the weight ratio of the first compound to the secondcompound is about 1:7.5.

Embodiment 60. The pharmaceutical composition of any one of Embodiments49-57, wherein the weight ratio of the first compound to the secondcompound is about 1:10.

Embodiment 61. The pharmaceutical composition of any one of Embodiments49-60, wherein the composition further comprises water and is suitablefor infusion.

Embodiment 62. A kit comprising the pharmaceutical combination of anyone of Embodiments 1-17.

Embodiment 63. A kit comprising the pharmaceutical composition of anyone of Embodiments 49-62.

Embodiment 64. A compound selected from the group consisting of

Embodiment 65. A crystalline polymorph of L-dopa 4′-monophosphateidentified by powder X-ray diffraction wherein the crystalline polymorphis:

-   -   crystalline L-dopa 4′-monophosphate anhydrate (i) demonstrating        at least one characteristic peak in the powder X-ray diffraction        pattern at values of two theta of 10.261±0.20, 12.053±0.20,        13.759±0.20, 14.932±0.20, 16.147±0.20, 16.718±0.20, 17.34±0.20,        19.254±0.20, 20.654±0.20, 22.078±0.20, 23.599±0.20, 24.198±0.20,        25.898±0.20, 26.338±0.20, and 27.117±0.20; or    -   crystalline L-dopa 4′-monophosphate anhydrate (ii) demonstrating        at least one characteristic peak in the powder X-ray diffraction        pattern at values of two theta of 8.468±0.20, 10.234±0.20,        11.821±0.20, 13.084±0.20, 13.503±0.20, 15.48±0.20, 15.848±0.20,        16.513±0.20, 18.447±0.20, 19.346±0.20, 20.239±0.20, 21.139±0.20,        24.221±0.20, 24.865±0.20, 25.647±0.20.

Embodiment 66. A crystalline L-dopa 3′-monophosphate demonstrating atleast one characteristic peak in the powder X-ray diffraction pattern atvalues of two theta of 8.662±0.20, 11.286±0.20, 15.079±0.20,15.678±0.20, 16.786±0.20, 17.288±0.20, 18.438±0.20, 19.682±0.20,20.946±0.20, 22.188±0.20, 22.671±0.20, 23.088±0.20, 24.144±0.20,24.744±0.20, and 25.383±0.20.

Embodiment 67. A crystalline L-dopa 3′4-diphosphate trihydratedemonstrating at least one characteristic peak in the powder X-raydiffraction pattern at values of two theta of 7.118±0.20, 10.342±0.20,11.355±0.20, 12.161±0.20, 14.201±0.20, 17.36±0.20, 17.632±0.20,19.196±0.20, 19.444±0.20, 20.83±0.20, 21.504±0.20, 22.491±0.20,23.085±0.20, 24.487±0.20, and 25.11±0.20.

Embodiment 68. A crystalline polymorph of carbidopa 4′-monophosphateidentified by powder X-ray diffraction wherein the crystalline polymorphis:

-   -   crystalline carbidopa 4′-monophosphate trihydrate demonstrating        at least one characteristic peak in the powder X-ray diffraction        pattern at values of two theta of 7.484±0.20, 10.05±0.20,        11.971±0.20, 13.085±0.20, 14.923±0.20, 16.095±0.20, 16.85±0.20,        17.359±0.20, 17.635±0.20, 19.269±0.20, 19.544±0.20, 21.842±0.20,        22.578±0.20, 22.921±0.20, and 23.822±0.20;    -   crystalline carbidopa 4′-monophosphate dihydrate demonstrating        at least one characteristic peak in the powder X-ray diffraction        pattern at values of two theta of 7.925±0.20, 10.28±0.20,        12.344±0.20, 15.002±0.20, 15.841±0.20, 16.158±0.20, 17.565±0.20,        18.506±0.20, 19.058±0.20, 19.473±0.20, 19.702±0.20, 20.188±0.20,        20.668±0.20, 22.37±0.20, and 24.167±0.20; or    -   crystalline carbidopa 4′-monophosphate dehydrate demonstrating        at least one characteristic peak in the powder X-ray diffraction        pattern at values of two theta of 9.492±0.20, 10.528±0.20,        15.356±0.20, 15.907±0.20, 16.165±0.20, 17.933±0.20, 18.737±0.20,        19.429±0.20, 21.176±0.20, and 22.626±0.20.

Embodiment 69. A crystalline polymorph of carbidopa 3′-monophosphateidentified by powder X-ray diffraction wherein the crystalline polymorphis:

-   -   crystalline carbidopa 3′-monophosphate (i) demonstrating at        least one characteristic peak in the powder X-ray diffraction        pattern at values of two theta of 9.171±0.20, 13.539±0.20,        14.23±0.20, 15.589±0.20, 15.979±0.20, 18.394±0.20, 18.832±0.20,        19.315±0.20, 22.143±0.20, and 22.81±0.20; or    -   crystalline carbidopa 3′-monophosphate (ii) demonstrating at        least one characteristic peak in the powder X-ray diffraction        pattern at values of two theta of 4.433±0.20, 8.917±0.20,        9.654±0.20, 13.192±0.20, 15.288±0.20, 15.747±0.20, 17.886±0.20,        19.291±0.20, 20.554±0.20, and 21.797.

Embodiment 70. A crystalline carbidopa 3′4-diphosphate sodium saltdemonstrating at least one characteristic peak in the powder X-raydiffraction pattern at values of two theta of 5.852±0.20, 6.861±0.20,7.338±0.20, 11.159±0.20, 11.729±0.20, 12.953±0.20, 13.714±0.20,14.381±0.20, 14.686±0.20, 15.479±0.20, 16.676±0.20, 17.179±0.20,17.592±0.20, 18.861±0.20 and 20.305±0.20.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents.

Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art. Such changes and modifications,including without limitation those relating to the chemical structures,substituents, derivatives, intermediates, syntheses, compositions,formulations, or methods of use of the invention, may be made withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. A pharmaceutical combination comprising a firstcompound corresponding in structure to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂; and a second compound corresponding in structureFormula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R³ and R⁴ is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂.
 2. The pharmaceutical combination of claim 1,wherein the first compound is selected from the group consisting of

and the second compound is selected from the group consisting of


3. The pharmaceutical combination of claim 1, wherein the first compoundis

and the second compound is


4. The pharmaceutical combination of claim 1, wherein the first compoundis

and the second compound is


5. The pharmaceutical combination of claim 1, wherein the first compoundis

and the second compound is


6. The pharmaceutical combination of claim 1, wherein the first compoundis

and the second compound is


7. The pharmaceutical combination of claim 1, wherein a weight ratio ofthe first compound or pharmaceutically acceptable salt thereof to thesecond compound or pharmaceutically acceptable salt thereof is fromabout 1:4 to about 1:10.
 8. The pharmaceutical combination of claim 1,wherein the combination is an aqueous combination suitable forintragastric, subcutaneous, intramuscular, intrajejunum, oral,intranasal or intravenous administration.
 9. The pharmaceuticalcombination of claim 1, wherein the combination is an aqueouscombination suitable for subcutaneous administration.
 10. A compoundcorresponding in structure to Formula (I):

or a pharmaceutically acceptable salt thereof, wherein R¹ and R² areeach independently selected from the group consisting of hydrogen,—P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₄-alkyl; R⁶ is hydrogen ora C₁-C₄-alkyl; and provided that at least one of R¹ and R² is —P(O)(OH)₂or —R⁵—O—P(O)(OH)₂.
 11. The compound or pharmaceutically acceptable saltof claim 10, wherein R¹ and R² are each independently selected from thegroup consisting of hydrogen, —P(O)(OH)₂, and —R⁵—O—P(O)(OH)₂; R⁵ is aC₁-C₂-alkyl; R⁶ is hydrogen; and provided that at least one of R¹ and R²is —P(O)(OH)₂ or —R⁵—O—P(O)(OH)₂.
 12. The compound or pharmaceuticallyacceptable salt of claim 10, wherein R¹ and R² are each independentlyhydrogen or —P(O)(OH)₂; R⁶ is hydrogen; and one of R¹ and R² is—P(O)(OH)₂.
 13. The compound or pharmaceutically acceptable salt ofclaim 10, wherein R¹ and R² are each independently hydrogen or—R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₂-alkyl; R⁶ is hydrogen; and provided thatone of R¹ and R² is —R⁵—O—P(O)(OH)₂.
 14. The compound orpharmaceutically acceptable salt of claim 10, wherein R¹ and R² are eachindependently hydrogen, —P(O)(OH)₂ or —R⁵—O—P(O)(OH)₂; R⁵ is aC₁-C₂-alkyl; R⁶ is a C₁-C₂-alkyl; and provided that one of R¹ and R² is—P(O)(OH)₂ or —R⁵—O—P(O)(OH)₂.
 15. A compound corresponding in structureto Formula (II):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areeach independently hydrogen or —R⁵—O—P(O)(OH)₂; R⁵ is a C₁-C₂-alkyl; R⁶is hydrogen; and provided that one of R³ and R⁴ is —R⁵—O—P(O)(OH)₂. 16.A method of treating Parkinson's disease comprising administering to asubject in need thereof a therapeutically effective amount of thepharmaceutical combination according to claim
 1. 17. The method of claim16, wherein the first compound is selected from the group consisting of

and the second compound is selected from the group consisting of


18. The method of claim 16, further comprising administering anotheranti-Parkinson's agent to the subject.
 19. The method of claim 16,wherein the pharmaceutical combination is an aqueous combination. 20.The method of claim 19, wherein the aqueous pharmaceutical combinationis administered by intragastric, subcutaneous, intramuscular,intranasal, intrajejunum, oral or intravenous administration.
 21. Themethod of claim 20, wherein the aqueous pharmaceutical combination isadministered by subcutaneous administration.
 22. The method of claim 21,wherein the method comprises substantially continuous administration ofthe pharmaceutical combination over a period of at least about 12 hours.23. A kit comprising the pharmaceutical combination of claim
 1. 24. Acompound selected from the group consisting of